ELLESTE DUET 1MG

Active substance: NORETHISTERONE ACETATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Elleste Duet 1mg

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One white tablet contains 1mg estradiol (as estradiol hemihydrate)
One green tablet contains 1mg estradiol (as estradiol hemihydrate) and 1mg
norethisterone acetate.
For excipients, see 6.1

3

PHARMACEUTICAL FORM
Film coated tablets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in
post- and 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

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.
Elderly
There are no special dosage requirements in elderly patients.
Children
Not to be used in children.
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.

4.3

Contraindications
Known, past or suspected breast cancer;
Known or suspected estrogen-dependent malignant tumours (e.g. endometrial
cancer);
Undiagnosed genital bleeding;
Untreated endometrial hyperplasia;
Previous idiopathic or current venous thromboembolism (deep venous thrombosis,
pulmonary embolism);
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;

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.
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 contraindications and warnings 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 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
A history of, or risk factors for, thromboembolic disorders (see
below)
Risk factors for estrogen 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 if 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
The risk of endometrial hyperplasia and carcinoma is increased when estrogens
are administered alone for prolonged periods (see Section 4.8). The addition of
a progestogen for at least 12 days per cycle in non-hysterectomised women
greatly reduces this risk.
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
A randomised placebo-controlled trial, the Women’s Health Initiative Study (WHI),
and epidemiological studies, including the Million Women Study (MWS), have
reported an increased risk of breast cancer in women taking estrogens, estrogenprogestogen combinations or tibolone for HRT for several years (see Section 4.8).

For all HRT, an excess risk becomes apparent within a few years of use and
increases with duration of intake but returns to baseline within a few (at most
five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with conjugated equine
estrogens (CEE) or estradiol (E2) was greater when a progestogen was added,
either sequentially or continuously, and regardless of type of progestogen.
There was no evidence of a difference in risk between the different routes of
administration.
In the WHI study, the continuous combined conjugated equine estrogen and
medroxyprogesterone acetate (CEE + MPA) product used was associated
with breast cancers that were slightly larger in size and more frequently had
local lymph node metastases compared to placebo.
HRT, especially estrogen-progestogen combined treatment, increases the
density of mammographic images which may adversely affect the
radiological detection of breast cancer.

Venous Thromboembolism

HRT is associated with a higher relative risk of developing venous
thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.
One randomised controlled trial and epidemiological studies found a two- to
threefold higher risk for users compared with non-users. For non-users it is
estimated that the number of cases of VTE that will occur over a 5 year period
is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 6069 years. It is estimated that in healthy women who use HRT for 5 years, the
number of additional cases of VTE over a 5 year period will be between 2 and
6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15
(best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such
an event is more likely in the first year of HRT than later.
Generally recognised risk factors for VTE include a personal history or family
history, severe obesity (BMI>30 kg/m2) and systemic lupus erythematosus
(SLE). There is no consensus about the possible role of varicose veins in
VTE.
Patients with a history of VTE or known thrombophilic states have an
increased risk of VTE. HRT may add to this risk. Personal or strong family
history of thromboembolism or recurrent spontaneous abortion should be
investigated in order to exclude a thrombophilic predisposition. Until a
thorough evaluation of thrombophilic factors has been made or anticoagulant
treatment initiated, use of HRT in such patients should be viewed as
contraindicated. Those women already on anticoagulant treatment require
careful consideration of the benefit-risk of use of HRT.
The risk of VTE may be temporarily increased with prolonged immobilisation,
major trauma or major surgery. As in all postoperative patients, scrupulous
attention should be given to prophylactic measures to prevent VTE following
surgery. Where prolonged immobilisation is liable to follow elective surgery,
particularly abdominal or orthopaedic surgery to the lower limbs,
consideration should be given to temporarily stopping HRT 4 to 6 weeks
earlier, if possible. Treatment should not be restarted until the woman is
completely mobilised.
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, dyspnea).
Coronary Artery Disease
There is no evidence from randomised controlled trials of cardiovascular
benefit
with
continuous
combined
conjugated
estrogens
and
medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and
HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible
increased risk of cardiovascular morbidity in the first year of use and no
overall benefit. For other HRT products there are only limited data from
randomised controlled trials examining effects in cardiovascular morbidity or

mortality. Therefore, it is uncertain whether these findings also extend to
other HRT products.
Stroke
One large randomised clinical trial (WHI-trial) found, as a secondary outcome,
an increased risk of ischaemic stroke in healthy women during treatment with
continuous combined conjugated estrogens and MPA. For women who do not
use HRT, it is estimated that the number of cases of stroke that will occur over
a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000
women aged 60-69 years. It is estimated that for women who use conjugated
estrogen and MPA for 5 years, the number of additional cases will be between
0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and
9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether
the increased risk also extends to other HRT products.
Ovarian Cancer
Long-term (at least 5 to 10 years) use of estrogen-only HRT products in
hysterectomised women has been associated with an increased risk of ovarian
cancer in some epidemiological studies. It is uncertain whether long-term use of
combined HRT confers a different risk than estrogen-only products.

Other Conditions
Estrogens may cause fluid retention, and therefore patients with cardiac or renal
dysfunction should be carefully observed. Patients with terminal renal
insufficiency should be closely observed, since it is expected that the level of
circulating active ingredients in Elleste Duet 1 mg is increased.
Women with pre-existing hypertriglyceridaemia should be followed closely
during estrogen replacement or hormone replacement therapy, since rare cases of
large increases of plasma triglycerides leading to pancreatitis have been reported
with estrogen therapy in this condition.
Estrogens 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 radioimmunoassay). 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).
There is no conclusive evidence for improvement of cognitive function. There
is some evidence from the WHI trial of increased risk of probable dementia in
women who start using continuous combined CEE and MPA after the age of

65. It is unknown whether the findings apply to younger post-menopausal
women or other HRT products.
There is an increased risk of gall bladder disease in women receiving postmenopausal estrogens.
In rare cases benign, and in even rarer cases malignant liver tumours leading in
isolated cases to life-threatening intra-abdominal haemorrhage have been
observed after the use of hormonal substances such as those contained in Elleste
Duet 1mg. If severe upper abdominal complaints, enlarged liver or signs of
intra-abdominal haemorrhage occur, a liver tumour should be considered in the
differential diagnosis.
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 estrogens 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 estrogens and progestogens.
Clinically, an increased metabolism of estrogens 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
estrogens such as tests for thyroid function (see Section 4.4) or glucose
tolerance.

4.6

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 estrogens + 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
No adverse effects on the ability to drive or operate machines have been
reported.

4.8

Undesirable effects
Undesirable effects observed with estrogens and progestogens are detailed in
the following table. The effects are grouped according to system organ class.

Common (>1/100)

Organ group
Nausea, abdominal pain

Gastrointestinal

Uncommon
(>1/1,000,
<1/100)
Dyspepsia,
vomiting,
flatulence,
gallbladder
disease,
gallstones

Rare
(>1/10,000,
<1/1,000)

Alopecia, hirsutism,
rash, itching.

Skin
Headache

CNS
Urogenital
Cardiovascular

Miscellaneous

Dizziness,
migraine
Uterine
bleeding, Vaginal
increase in size of uterine candidiasis
fibroids
Increase
in Venous
blood
thromboembolism*
pressure
Thrombophlebitis
Weight
Leg cramps
increase/decrease,
oedema,
breast
tenderness,
breast
enlargement, change in
mood including anxiety
and depressive mood,
change in libido

* see Sections 4.3 Contraindications and 4.4 Special warnings and precautions for use

Breast Cancer
According to evidence from a large number of epidemiological studies and
one randomised placebo-controlled trial, the Women’s Health Initiative
(WHI), the overall risk of breast cancer increases with increasing duration of
HRT use in current or recent HRT users.
For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of
original data from 51 epidemiological studies (in which >80% of HRT use was
estrogen-only HRT) and from the epidemiological Million Women Study
(MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40),
respectively.
For estrogen plus progestogen combined HRT, several epidemiological
studies have reported an overall higher risk for breast cancer than with
estrogens alone.

The MWS reported that, compared to never users, the use of various types of
estrogen-progestogen combined HRT was associated with a higher risk of
breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone
(RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.251.68).
The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6
years of use of estrogen-progestogen combined HRT (CEE + MPA) in all
users compared with placebo.
The absolute risks calculated from the MWS and the WHI trial are presented
below:
The MWS has estimated, from the known average incidence of breast cancer
in developed countries, that:
For women not using HRT, about 32 in every 1000 are expected to have
breast cancer diagnosed between the ages of 50 and 64 years.
For 1000 current or recent users of HRT, the number of additional cases
during the corresponding period will be
For users of estrogen-only replacement therapy
• between 0 and 3 (best estimate = 1.5) for 5 years’ use
• between 3 and 7 (best estimate = 5) for 10 years’ use.
For users of estrogen plus progestogen combined HRT,
• between 5 and 7 (best estimate = 6) for 5 years’ use
• between 18 and 20 (best estimate = 19) for 10 years’ use.
The WHI trial estimated that after 5.6 years of follow-up of women between
the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer
would be due to estrogen-progestogen combined HRT (CEE + MPA) per
10,000 women years.
According to calculations from the trial data, it is estimated that:
For 1000 women in the placebo group,
• about 16 cases of invasive breast cancer would be diagnosed in 5 years.
For 1000 women who used estrogen + progestogen combined HRT (CEE
+ MPA), the number of additional cases would be
• between 0 and 9 (best estimate = 4) for 5 years’ use.
The number of additional cases of breast cancer in women who use HRT is
broadly similar for women who start HRT irrespective of age at start of use
(between the ages of 45-65) (see Section 4.4).

Endometrial cancer
In women with an intact uterus, the risk of endometrial hyperplasia and
endometrial cancer increases with increasing duration of use of unopposed
estrogens. According to data from epidemiological studies, the best estimate
of the risk is that for women not using HRT, about 5 in every 1000 are
expected to have endometrial cancer diagnosed between the ages of 50 and 65.
Depending on the duration of treatment and estrogen dose, the reported
increase in endometrial cancer risk among unopposed estrogen users varies

from 2-to 12-fold greater compared with non-users. Adding a progestogen to
estrogen-only therapy greatly reduces, this increased risk.
Very rare cases of myocardial infarction, stroke, chloasma, erythema
multiforme, erythema nodosum, vascular purpura, haemorrhagic eruption and
probable dementia (see Section 4.4) have been reported in women using HRT.

4.9

Overdose
Overdosage may be manifested by nausea and vomiting. If overdosage 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
overdosage and further treatment should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Progestogens and estrogens, sequential preparations,
norethisterone and estrogen.
ATC Code: G03FB05
Estradiol
The active ingredient, synthetic 17 -estradiol, is chemically and biologically identical
to endogenous human estradiol. It substitutes for the loss of estrogen production in
menopausal women, and alleviates menopausal symptoms.

β

Norethisterone acetate
As estrogens promote the growth of the endometrium, unopposed estrogens increase
the risk of endometrial hyperplasia and cancer. The addition of a progestogen
reduces but does not eliminate the estrogen-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

Norethisterone

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

mean (SD)

Estradiol
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.

5.3

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. feminisation of
male foetuses in high doses. Norethisterone acetate showed embryotoxic effects and
induced anomalies in urogenital tract development. In mice, additional anomalies in
non-urogenital foetal development, including hydrocephalus and clubfoot, have been
detected.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Lactose monohydrate, maize starch, povidone 25, talc (purified) and magnesium
stearate
Film-coating material:
Estradiol only (white) tablets:
Hydroxypropylmethyl cellulose (E464), titanium dioxide (E171) and macrogol 400
Estradiol and Norethisterone Acetate only (green) tablets:
Hydroxypropylmethyl cellulose (E464), titanium dioxide (E171), macrogol 400,
quinoline yellow (E104) and 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 tablets and 84 (3 x 28) tablets.

6.6

Special precautions for disposal
There are no special instructions for handling.

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
27/08/2007

10

DATE OF REVISION OF THE TEXT
04/07/2013

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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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