ANGELIQ FILM-COATED TABLETS

Active substance: ESTRADIOL HEMIHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Angeliq film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film coated tablet contains 1 mg estradiol (as estradiol hemihydrate) and
2 mg drospirenone.
Excipient: 46 mg lactose
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablet
Medium red, round tablet with convex faces, one side embossed with the letters DL in
a regular hexagon.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Hormone replacement therapy for oestrogen deficiency symptoms in
postmenopausal women more than 1 year post menopause.
Prevention of osteoporosis in postmenopausal women at high risk of future
fractures who are intolerant of, or contraindicated for, other medicinal
products approved for the prevention of osteoporosis.
(See also section 4.4)
The experience treating women older than 65 years is limited.

4.2

Posology and method of administration

Women who do not take hormone replacement therapy (HRT) or women who change
from another continuous combined product may start treatment at any time. Women
changing from a cyclic, sequential combined HRT regimen, treatment should begin
the day following completion of the prior regimen.
Dosage
One tablet is taken daily. Each blister is for 28 days of treatment.
Administration
The tablets are to be swallowed whole with some liquid irrespective of food intake.
Treatment is continuous, which means that the next pack follows immediately
without a break. The tablets should preferably be taken at the same time every day. If
a tablet is forgotten it should be taken as soon as possible. If more than 24 hours have
elapsed no extra tablet needs to be taken. If several tablets are forgotten, vaginal
bleeding may occur.
For treatment of post menopausal symptoms, the lowest effective dose should be
used.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest
effective dose for the shortest duration (see also section 4.4) should be used.
Additional information on special populations
Children and adolescents
Angeliq is not indicated for use in children and adolescents.
Geriatric patients
There are no data suggesting a need for dosage adjustment in elderly patients. In
women aged 65 years or older, see section 4.4.
Patients with hepatic impairment
In women with mild or moderate hepatic impairment, drospirenone is well tolerated
(see 5.2.Pharmacokinetic properties). Angeliq is contraindicated in women with
severe hepatic disease (see 4.3).
Patients with renal impairment
In women with mild or moderate renal impairment, a slight increase of drospirenone
exposure was observed but is not expected to be of clinical relevance (see 5.2).
Angeliq is contraindicated in women with severe renal disease (see 4.3).

4.3

Contraindications


Undiagnosed genital bleeding



Known, past or suspected cancer of the breast



Known or suspected oestrogen-dependent
endometrial cancer)
Untreated endometrial hyperplasia



malignant

tumours

(e.g.





Active or recent arterial thromboembolic disease (e.g. angina, myocardial
infarction)



High risk of venous or arterial thrombosis



Presence or history of liver tumors (benign or malignant)



Severe hepatic disease



Severe renal insufficiency or acute renal failure



Known hypersensitivity to the active substances or to any of the excipients



4.4

Previous or current venous thromboembolism (deep venous thrombosis,
pulmonary embolism)

Severe hypertriglyceridaemia

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 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. 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 Angeliq, 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)
In rare cases benign, and even more rarely, malignant liver tumors have been
observed after the use of hormonal substances such as those contained in
HRT products. In isolated cases, these tumors led to life-threatening intraabdominal hemorrhage.
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
Porphyria

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 12-fold greater compared with nonusers, 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-progestagen therapy in non-hysterectomised
women prevents the excess risk associated with oestrogen-only HRT.
Breakthrough bleeding and spotting may occur during the first months of treatment. If
breakthrough 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 oestrogenprogestagen and possibly also oestrogen-only HRT, that is
dependent on the duration of taking HRT.
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 oestrogenprogestagen for HRT that becomes
apparent after about 3 years (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.
Venous thromboembolism
HRT is associated with a 1.3-to-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)..
Generally recognised risk factors for VTE include a personal history or family history
(the occurrence of VTE in a direct relative at a relatively early age may indicate
genetic disposition) and, severe obesity.. The risk of VTE also increases with age.
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 and HRT may add to this risk. HRT is therefore contraindicated in these
patients (see section 4.3).
The risk of VTE may be temporarily increased with prolonged immobilisation, major
elective or post-traumatic surgery or major trauma. Depending on the nature of the
event and the duration of the immobilization, consideration should be given to a
temporary discontinuation of HRT.
The potential for an increased synergistic risk of thrombosis should be considered in
women who possess a combination of risk factors or exhibit a greater severity of an
individual risk factor. This increased risk may be greater than a simple cumulative
risk of the factors. HRT should not be prescribed in case of a negative risk benefit
assessment.
Women already on chronic 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 and progestagen or oestrogen-only HRT.
The relative risk of CAD during use of combined oestrogen and progestagen 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 and progestagen use is very low
in healthy women close to menopause, but will rise with more advanced age.
Ischaemic stroke
Combined oestrogen-progestagen 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).
Ovarian cancer
Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use
of oestrogen-only HRT products has been associated with a slightly increased risk of
ovarian cancer (see section 4.8). Some studies, including the WHI trial, suggest that
the long-term use of combined HRT may confer a similar or slightly smaller risk (see
setion 4.8).
Other conditions
Women with moderately elevated levels of triglycerides need special surveillance. ,
HRT in these women may be associated with a further increase of triglyceride levels
bearing the risk of acute pancreatitis..
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 radioimmunoassay) 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-I-antitrypsin, ceruloplasmin).
HRT use 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.
The progestin component in Angeliq is an aldosterone antagonist exhibiting weak
potassium sparing properties. In most cases, no increase of serum potassium levels is
to be expected. In a clinical study, however, in some patients with mild or moderate
renal impairment and concomitant use of potassium-sparing medicinal products (such
as ACE inhibitors, angiotensin II receptor antagonists or NSAIDs) serum potassium
levels slightly, but not significantly increased during drospirenone intake. Therefore,
it is recommended to check serum potassium during the first month of treatment in
patients presenting with renal insufficiency and pretreatment serum potassium in the
upper reference range, and particularly during concomitant use of potassium sparing
medicinal products (see also section 4.5).
Women with elevated blood pressure may experience a decrease in blood pressure
under treatment with Angeliq due to the aldosterone antagonist activity of
drospirenone (see section 5.1). Angeliq should not be used to treat hypertension.
Women with hypertension should be treated according to hypertension guidelines.
Chloasma may occasionally occur, especially in women with a history of chloasma
gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or
ultraviolet radiation whilst taking HRT.
Close medical supervision (including periodic measurement of prolactin levels) is
necessary if the patient suffers from prolactinoma.

Each tablet of this medicinal product contains 46 mg lactose per tablet. Patients with
rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption who are on a lactose-free diet should take this
amount into consideration.

4.5

Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on Angeliq
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, carbamezapine) 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 main metabolites of drospirenone are generated without involvement of
the cytochrome P450 system. Inhibitors of this enzyme system are therefore
unlikely to influence the metabolism of drospirenone.
Interaction of Angeliq with other medicinal products
Based on in vitro inhibition studies and on in vivo interaction studies in female
volunteers receiving steady-state doses of 3 mg drospirenone per day and
omeprazole, simvastatin, or midazolam as marker substrate, a clinically
relevant interaction of drospirenone with the cytochrome P450 enzyme
mediated metabolism of other drugs is unlikely.
Concomitant use of Angeliq and either NSAIDs or ACE inhibitors /
angiotensin II receptor antagonists is unlikely to increase serum potassium.
However, concomitant use of all these three types of medications together may
cause a small increase in serum potassium, which is more pronounced in
diabetic women.
Hypertensive women treated with Angeliq and antihypertensive medications
may experience an additional decrease in blood pressure (see section 4.4).

4.6

Pregnancy and lactation

Pregnancy
Angeliq is not indicated during pregnancy. If pregnancy occurs during
medication with Angeliq, treatment should be discontinued promptly. No
clinical data on exposed pregnancies are available for drospirenone. Animal
studies have shown reproductive toxicity (see section 5.3). The potential risk
for humans is unknown. The results of most epidemiological studies to date
relevant to inadvertent foetal exposure to combinations of oestrogens with
other progestogens have not indicated a teratogenic or foetotoxic effect.
Lactation
Angeliq is not indicated during lactation.
4.7
Effects on ability to drive and use machines
No effects on the ability to drive and use machines have been observed.

4.8

Undesirable effects
The table below reports adverse reactions by MedDRA system organ classes
(MedDRA SOCs). The frequencies are based on clinical trial data. The adverse
reactions were recorded in 7 Phase III clinical studies (n=2424 women) and
considered as at least possibly causally related to Angeliq (E2 1 mg / DRSP doses
0.5, 1, 2, or 3 mg).
The most commonly reported adverse reactions were breast pain (> 10%) and during
the first few months of treatment, bleeding and spotting (> 10%). Bleeding
irregularities usually subside during continued treatment (see section 5.1). The
frequency of bleeding decreases with the duration of treatment.
System Organ
Class

Common
(≥ 1/100 to < 1/10)

Blood and
lymphatic system
disorders
Metabolism and
nutrition disorders

Psychiatric disorders Depression, emotional
lability, nervousness
Nervous system
Headache
disorders
Eye disorders
Ear and labyrinth
disorders
Cardiac disorders

Uncommon
(≥ 1/1000 to < 1/100)

Rare
(< 1/1000)
Anemia

Weight increase or
weight decrease,
anorexia, increased
appetite, hyperlipemia
Sleep disorder, anxiety,
libido decreased
Paresthesia,
concentration ability
impaired, dizziness
Eye disorder, visual
disturbance

Vertigo

Tinnitus
Palpitation

System Organ
Class

Common
(≥ 1/100 to < 1/10)

Vascular disorders

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Uncommon
(≥ 1/1000 to < 1/100)

Rare
(< 1/1000)

Embolism, venous
thrombosis,
hypertension, migraine,
thrombophlebitis,
varicose veins
Dyspnoea

Abdominal pain, nausea, Gastrointestinal
abdomen enlarged
disorder, diarrhea,
constipation, vomiting,
dry mouth, flatulence,
taste disturbance
Hepatobiliary
Liver function test
disorders
abnormal
Skin and
Skin disorder, acne,
subcutaneous tissue
alopecia, pruritus, rash,
disorders
hirsutism, hair disorder
Musculoskeletal and
Pain in extremity, back
connective tissue
pain, arthralgia, muscle
disorders
cramps
Renal and urinary
Urinary tract disorder,
disorders
urinary tract infection
Reproductive
Benign breast neoplasm, Breast carcinoma,
system and breast
breast enlargement,
endometrial hyperplasia,
disorders
uterine fibroids
benign uterine
enlarged, benign
neoplasm, fibrocystic
neoplasm of cervix uteri, breast, uterine disorder,
menstrual disorder,
ovarian disorder, cervix
vaginal discharge
disorder, pelvic pain,
vulvovaginal disorder,
vaginal candidiasis,
vaginitis, vaginal
dryness
General disorders
Asthenia, localized
Generalized oedema,
and administration
oedema
chest pain, malaise,
site conditions
sweating increased

Cholelithiasis

Myalgia

Salpingitis,
galactorrhoea

Chills

The most appropriate MedDRA term is used to describe a certain reaction and its
synonyms and related conditions.
Additional information on special populations
The following, undesirable effects classified as at least possibly related to Angeliq
treatment by the investigator, were recorded in 2 clinical studies in hypertensive
women.
Metabolism and nutrition disorders
Hyperkalemia
Cardiac disorders

Cardiac failure, atrial flutter, QT interval prolonged, cardiomegaly
Investigations
Blood aldosterone increased.
The following undesirable effects have been reported in association with HRT
products: Erythema nodosum, eythema multiforme, chloasma and hemorrhagic
dermatitis.
Breast cancer risk
An up to 2-fold increased risk of having breast cancer diagnosed is reported in
women taking combined oestrogen-progestagen 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-progestagen 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
of use
Age range
(years)

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

Risk ratio & 95% CI b

Additional cases per
1000 HRT users over
5 years (95% CI)
1 - 2 (0 - 3)

Oestrogen-only HRT
1.2
Combined oestrogen-progestagen
50 - 65
9 - 12
1.7
6 (5 - 7)
a Taken from baseline incidences in developed countries.
b Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.
Note: Since the background incidence of breast cancer differs by EU country, the number of
additional cases of breast cancer differs by EU country, the number of additional cases of breast
cancer will also change proportionately.
50 - 65

9 - 12

US WHI studies - additional risk of breast cancer after 5 years of use
Age range
(years)

Incidence per 1000 women in
placebo arm over 5 years

Risk ratio & 95%
CI

50 - 79

21

CEE oestrogen-only
0.8 (0.7 – 1.0)

Additional cases per
1000 HRT users over 5
years (95% CI)
-4 (-6 - 0) a

CEE + MPA oestrogen & progestagen b
50 - 79
14
1.2 (1.0 – 1.5)
+4 (0 - 9)
a WHI study in women with no uterus, which did not show an increased in risk of breast cancer.
b 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 an 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 10 and 60 extra cases diagnosed
in every 1000 women between the ages of 50 and 65.
Adding a progestagen 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
Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been
associated with a slightly increased risk of ovarian cancer. In the Million Women
Study 5 years of HRT resulted in 1 extra case per 2500 users.
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 of use
Age range
(years)
50 - 59

Incidence per 1000 women in
placebo arm over 5 years
7

50 - 59
4
a Study in women with no uterus.

Risk ratio & 95% CI
Oral oestrogen-only a
1.2 (0.6 – 2.4)

Additional cases per
1000 HRT users
1 (-3 - 10)

Oral combined oestrogen & progestagen b
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-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke
The use of oestrogen-only and oestrogen-progestagen 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 agedependent, 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 a over 5 years of use
Age range
(years)

Incidence per 1000 women in
placebo arm over 5 years

Risk ratio & 95%
CI

Additional cases per
1000 HRT Users over 5
years

50 - 59

8

1.3 (1.1 – 1.6)

3 (1 – 5)

a No differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions have been reported in association with oestrogen/progestogen
treatment
- Gall bladder disease.
- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema
nodosum, vascular purpura.
- Probable dementia over the age of 65 (see section 4.4).

4.9
Overdose
In clinical studies in male volunteers doses up to 100 mg of drospirenone were well
tolerated. Based on general experience with combined oral contraceptives, symptoms
that may possibly occur are nausea and vomiting and – in young girls and some
women – vaginal bleeding. There are no specific antidotes, and, therefore, treatment
should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: progestogens and estrogens, combinations. ATC
code: G03FA17
Estradiol
Angeliq contains synthetic 17ß-estradiol, which is chemically and biologically
identical to endogenous human estradiol. It substitutes for the loss of
oestrogen production in menopausal women, and alleviates menopausal
symptoms. Oestrogens prevent bone loss following menopause or
ovariectomy.

Drospirenone
Drospirenone is a synthetic progestogen.
As oestrogens promote the growth of the endometrium, unopposed oestrogens
increase the risk of endometrial hyperplasia and cancer. The addition of a
progestogen reduces, but does not eliminate the oestrogen-induced risk of
endometrial hyperplasia in non-hysterectomised women.
Drospirenone displays aldosterone antagonist activity. Therefore, increases in
sodium and water excretion and decreases in potassium excretion may be
observed.
In animal studies, drospirenone has no oestrogenic, glucocorticoid or
antiglucocorticoid activity.
Clinical trial information


Relief of oestrogen-deficiency symptoms and bleeding patterns
Relief of menopausal symptoms was achieved during the first few
weeks of treatment.
Amenorrhea was seen in 73% of the women during months 10-12 of
treatment. Breakthrough bleeding and /or spotting appeared in 59% of
the women during the first three months of treatment and in 27%
during months 10-12 of treatment.



Prevention of osteoporosis
Oestrogen deficiency at menopause is associated with an increasing
bone turnover and decline in bone mass. The effect of oestrogen on the
bone mineral density is dose-dependent. Protection appears to be
effective as long as treatment is continued. After discontinuation of
HRT, bone mass is lost at a rate similar to that in untreated women.
Evidence from WHI trial and meta-analysed trials shows that current
use of HRT, alone or in combination with a progestogen – given to
predominantly healthy women – reduces the risk of hip, vertebral, and
other osteoporotic fractures. HRT may also prevent fractures in women
with low bone density and/or established osteoporosis, but the
evidence for that is limited.
After 2 years of treatment with Angeliq, the increase in hip bone
mineral density (BMD) was 3.96 +/- 3.15% (mean +/- SD) in
osteopenic patients and 2.78 +/- 1.89% (mean +/- SD) in nonosteopenic patients. The percentage of women who maintained or
gained BMD in hip zone during treatment was 94.4% in osteopenic
patients and 96.4% in non-osteopenic patients.
Angeliq also had an effect on lumbar spine BMD. The increase after 2
years was 5.61 +/- 3.34% (mean +/- SD) in osteopenic women and
4.92+/- 3.02% (mean +/- SD) in non-osteopenic women. The
percentage of osteopenic women who maintained or gained BMD in
lumbar zone during treatment was 100% , whereas this percentage was
96.4% in non-osteopenic women.



Antimineralocorticoid activity
DRSP has aldosterone antagonistic properties that can result in a
decrease in blood pressure in hypertensive women. In a double-blind
placebo-controlled trial hypertensive postmenopausal women treated
with Angeliq (n=123) for 8 weeks experienced a significant decrease in
systolic/diastolic blood pressure values (office cuff versus baseline 12/-9 mm Hg, corrected for placebo effect -3/-4 mm Hg; 24h
ambulatory blood pressure measurement versus baseline -5/--3 mm Hg,
corrected for placebo effect -3/-2 mm Hg).
Angeliq should not be used to treat hypertension. Women with
hypertension should be treated according to hypertension guidelines.

5.2

Pharmacokinetic properties
Drospirenone


Absorption

After oral administration drospirenone is rapidly and completely absorbed.
With a single administration, peak serum levels of approx. 21.9 ng/ml are
reached about 1 hour after ingestion. After repeated administration, a
maximum steady-state concentration of 35.9 ng/ml is reached after about 10
days. The absolute bioavailability is between 76 and 85%. Concomitant
ingestion of food had no influence on the bioavailability.


Distribution

After oral administration, serum drospirenone levels decrease in two phases
which are characterised by a mean terminal half-life of about 35–39 hours.
Drospirenone is bound to serum albumin and does not bind to sex hormone
binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of
the total serum drug concentrations are present as free steroid. The mean
apparent volume of distribution of drospirenone is 3.7-4.2 l/kg.


Metabolism

Drospirenone is extensively metabolized after oral administration. The major
metabolites in the plasma are the acid form of drospirenone, generated by
opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulphate, both
of which are formed without involvement of the P450 system. Both major
metabolites are pharmacologically inactive. Drospirenone is metabolized to a
minor extent by cytochrome P450 3A4 based on in vitro data. In vitro and
clinical studies do not indicate an inhibitory effect of DRSP on CYP enzymes
after administration of Angeliq.



Elimination

The metabolic clearance rate of drospirenone in serum is 1.2-1.5 ml/min/kg
showing an intersubject variability of about 25%. Drospirenone is excreted
only in trace amounts in unchanged form. The metabolites of drospirenone are
excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The
half-life of metabolite excretion with the urine and faeces is about 40 hours.


Steady-state conditions and linearity

Following daily oral administration of Angeliq, drospirenone concentrations
reached a steady-state after about 10 days. Serum drospirenone levels
accumulated by a factor of about 2 to 3 as a consequence of the ratio of
terminal half-life and dosing interval. At steady-state, mean serum levels of
drospirenone fluctuate in the range of 14–36 ng/ml after administration of
Angeliq. Pharmacokinetics of drospirenone are dose-proportional within the
dose range of 1 to 4 mg.
Estradiol


Absorption

Following oral administration, estradiol is rapidly and completely absorbed.
During the absorption and the first liver passage, estradiol undergoes extensive
metabolism, thus reducing the absolute bioavailability of oestrogen after oral
administration to about 5% of the dose. Maximum concentrations of about
22 pg/ml were reached 6-8 hours after single oral administration of Angeliq.
The intake of food had no influence on the bioavailability of estradiol as
compared to drug intake on an empty stomach.


Distribution

Following oral administration of Angeliq only gradually changing serum
levels of estradiol are observed within an administration interval of 24 hours.
Because of the large circulating pool of oestrogen sulphates and glucuronides
on the one hand and the enterohepatic recirculation on the other hand, the
terminal half-life of estradiol represents a composite parameter that is
dependent on all of these processes and is in the range of about 13-20 hours
after oral administration.
Estradiol is bound non-specifically to serum albumin and specifically to
SHBG. Only about 1-2% of the circulating Estradiol is present as free steroid,
40-45% is bound to SHBG. The apparent volume of distribution of estradiol
after single intravenous administration is about 1 l/kg.


Metabolism

Estradiol is rapidly metabolized, and besides oestrone and oestrone sulphate, a
large number of other metabolites and conjugates are formed. Oestrone and
oestriol are known as pharmacologically active metabolites of estradiol; only

oestrone occurs in relevant concentrations in plasma. Oestrone reaches about
6-fold higher serum levels than estradiol. The serum levels of the oestrone
conjugates are about 26-times higher than the corresponding concentrations of
free oestrone.


Elimination

The metabolic clearance has been found to be about 30 ml/min/kg. The
metabolites of estradiol are excreted via urine and bile with a half-life of about
1 day.


Steady-state conditions

Following daily oral administration of Angeliq, estradiol concentrations
reached a steady-state after about five days. Serum estradiol levels accumulate
approx. 2-fold. Orally administered estradiol induces the formation of SHBG
which influences the distribution with respect to the serum proteins, causing
an increase of the SHBG-bound fraction and a decrease in the albumin-bound
and unbound fraction indicating non-linearity of the pharmacokinetics of
estradiol after ingestion of Angeliq. With a dosing interval of 24 hours, mean
steady-state serum levels of estradiol fluctuate in the range of 20-43 pg/ml
following administration of Angeliq. Pharmacokinetics of estradiol are doseproportional at doses of 1 and 2 mg.
Special populations


Hepatic impairment

The pharmacokinetics of a single oral dose of 3 mg DRSP in combination with
1 mg estradiol (E2) was evaluated in 10 female patients with moderate hepatic
impairment (Child Pugh B) and 10 healthy female subjects matched for age,
weight, and smoking history. Mean serum DRSP concentration-time profiles
were comparable in both groups of women during the absorption/ distribution
phases with similar Cmax and tmax values, suggesting that the rate of
absorption was not affected by the hepatic impairment. The mean terminal
half-life was about 1.8-times greater and an about 50% decrease in apparent
oral clearance (CL/f) was seen in volunteers with moderate hepatic
impairment as compared to those with normal liver function.


Renal impairment

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily
for 14 days) were investigated in female subjects with normal renal function
and mild and moderate renal impairment. At steady-state of DRSP treatment,
serum DRSP levels in the group with mild renal impairment (creatinine
clearance CLcr, 50-80 ml/min) were comparable to those in the group with
normal renal function (CLcr, > 80 ml/min). The serum DRSP levels were on
average 37% higher in the group with moderate renal impairment (CLcr, 3050 ml/min) compared to those in the group with normal renal function. Linear

regression analysis of the DRSP AUC(0-24 hours) values in relation to the
creatinine clearance revealed a 3.5% increase with a 10 ml/min reduction of
creatinine clearance. This slight increase is not expected to be of clinical
relevance.
5.3

Preclinical safety data
Animal studies with estradiol and drospirenone have shown expected
oestrogenic and gestagenic effects. There are no preclinical data of relevance
to the prescriber that are additional to those already included in other sections
of the SPC.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Lactose monohydrate
Maize starch
Pregelatinised maize starch
Povidone
Magnesium stearate (E470b)
Film-coating material:
Hypromellose (E464)
Macrogol 6000
Talc (E553b)
Titanium dioxide (E171)
Ferric oxide, red (E172)

6.2
Incompatibilities
Not applicable

6.3
Shelf life
Five years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.
6.5

Nature and contents of container
Transparent polyvinyl film (250 µm) / aluminium foil (20 µm) blisters of 28
tablets with imprinted week days.
The pack sizes are 1x28 tablets and 3x28 tablets.

6.6
Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER

Bayer plc
Bayer House
Strawberry Hill
Newbury
Berkshire RG14 1JA

8

MARKETING AUTHORISATION NUMBER(S)

PL 00010/0518

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11/12/2007

10

DATE OF REVISION OF THE TEXT
09/10/2011

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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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