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TIBOLONE-MITHRA 2.5 MG TABLETS

Active substance(s): TIBOLONE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Tibolone-Mithra 2.5 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contain contains 2.5 mg tibolone.
Excipient(s) with known effect: each tablet contains 43.2 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
White to off-white round uncoated tablets of 6 mm diameter with bevelled edge
without any marking.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications


Treatment of oestrogen deficiency symptoms in postmenopausal women, more
than one year after 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 5.1)

For all women the decision to prescribe Tibolone-Mithra should be based on an
assessment of the individual patient’s overall risks and, particularly in the over 60s,
should include consideration of the risk of stroke (see sections 4.4 and 4.8).

4.2

Posology and method of administration
Posology
The dosage is one tablet per day. The tablets should be swallowed with some water or
other drink, preferably at the same time every day.
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.

A separate progestogen should not be added with Tibolone-Mithra treatment.
Starting Tibolone-Mithra
Women experiencing a natural menopause should commence treatment with
Tibolone-Mithra at least 12 months after their last natural bleed. In case of a surgical
menopause, treatment with Tibolone-Mithra may commence immediately. Women
being treated with gonadotrophin releasing hormone (GnRH) analogues, for example,
for endometriosis, may commence treatment with Tibolone-Mithra immediately.
Any irregular/unscheduled vaginal bleeding, either on or off HRT, should be
investigated to exclude malignancy before starting Tibolone-Mithra (see section 4.3)
Switching from a sequential or continuous combined HRT preparation
If changing from a sequential HRT preparation, treatment with Tibolone-Mithra
should start the day following completion of the prior regimen. If changing from a
continuous combined HRT preparation, treatment can start at any time.
Missed dose
A missed dose should be taken as soon as remembered, unless it is more than 12
hours overdue. In the latter case, the missed dose should be skipped and the next dose
should be taken at the normal time. Missing a dose may increase the likelihood of
breakthrough bleeding and spotting.
Paediatric population
There is no relevant use of Tibolone-Mithra in the paediatric population.
Elderly
No dose adjustment is necessary for the elderly. There is limited experience in
treating women over age 65 years.

Method of administration
For oral use

4.3

Contraindications
-

Pregnancy and lactation
Known, past or suspected breast cancer – Tibolone-Mithra increased the risk of
breast cancer recurrence in placebo controlled trial.
Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial
cancer)
Undiagnosed genital bleeding
Untreated endometrial hyperplasia
Previous or current venous thromboembolism (deep venous thrombosis,
pulmonary embolism)

-

4.4

Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin
deficiency, see section 4.4)
Any history of arterial thromboembolic disease (e.g. angina, myocardial
infarction, stroke or Transient Ischemic Attack (TIA))
Acute liver disease, or a history of liver disease as long as liver function tests
have failed to return to normal
Porphyria
Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1

Special warnings and precautions for use
For the treatment of postmenopausal symptoms, Tibolone-Mithra 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
Tibolone-Mithra should only be continued as long as the benefit outweighs the risk.
The risks of stroke, breast cancer and, in women with an intact uterus, endometrial
cancer (see below and section 4.8) for each woman should be carefully assessed, in
the light of her individual risk factors and bearing in mind the frequency and
characteristics of both cancers and stroke, in terms of their response to treatment,
morbidity and mortality.
Evidence regarding the risks associated with HRT or tibolone 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 or tibolone, 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 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 Tibolone-Mithra, 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
The available data from randomised controlled trials are conflicting, however,
observational studies have consistently shown that women who are prescribed
Tibolone-Mithra in normal clinical practice are at an increased risk of having
endometrial cancer diagnosed (see also Section 4.8). In these studies risk increased
with increasing duration of use. Tibolone increases endometrial wall thickness, as
measured by transvaginal ultrasound.
Break-through bleeding and spotting may occur during the first months of treatment
(see section 5.1). Women should be advised to report any break-through bleeding or
spotting if it is still present after 6 months of treatment, if it starts beyond that time or
if it continues after treatment has been discontinued. The woman should be referred
for gynaecological investigation, which is likely to include endometrial biopsy to
exclude endometrial malignancy.
Breast cancer
Evidence with respect to breast cancer risk in association with tibolone is
inconclusive. The Million Women Study (MWS) has identified a significant increase
in the risk of breast cancer in association with use of the 2.5mg dose. This risk
became apparent within a few years of use and increased with duration of intake,
returning to baseline within a few (at most five) years after stopping treatment (see
section 4.8). These results could not be confirmed in a study using the General
Practice Research Database (GPRD).
HRT, especially oestrogen-progestagen 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 Women's Health Initiative (WHI) trial, suggest that
the use of combined HRTs may be associated with a similar, or slightly smaller risk
(see section 4.8).
In the Million Women Study it was shown that the relative risk for ovarian cancer
with use of tibolone was similar to the risk associated with use of other types of HRT.
Venous thromboembolism
Oestrogen or oestrogen-progestogen 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). In an epidemiological study using a UK database, the risk
of VTE in association with tibolone was lower than the risk associated with
conventional HRT, but only a small proportion of women were current users of
tibolone and a small increase in risk compared with non-use cannot be excluded.
Patients with known thrombophilic states have an increased risk of VTE and HRT or
tibolone may add to this risk. HRT is therefore contraindicated in these patients (see
section 4.3).
Generally recognized 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 or
tibolone 4 to 6 weeks earlier is recommended, if possible. 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 or tibolone is
contraindicated.
Women already on anticoagulant treatment require careful consideration of the
benefit-risk of use of HRT or tibolone.
If VTE develops after initiating therapy, the drug should be discontinued. Patients
should be told to contact their doctor 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 (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. In an epidemiological
study using the GPRD no evidence was found of protection against myocardial
infarction in postmenopausal women who received tibolone.
Ischaemic stroke
Tibolone increases the risk of ischaemic stroke from the first year of treatment (see
section 4.8). The baseline risk of stroke is strongly age-dependent and so the effect of
tibolone is greater with older age.
Other conditions
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
Tibolone-Mithra is not intended for contraceptive use.
Treatment with Tibolone-Mithra results in a marked dose-dependent decrease in HDL
cholesterol (from -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2
years). Total triglycerides and lipoprotein(a) levels were also reduced. The decrease
in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C
were unchanged. The clinical implication of these findings is not yet known.
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 HRT, since rare cases of large increases of plasma
triglycerides leading to pancreatitis have been reported with oestrogen therapy in this
condition.
Treatment with Tibolone-Mithra results in a very minor decrease of thyroid binding
globulin (TBG) and total T4. Levels of total T3 are unaltered. Tibolone-Mithra
decreases the level of sexhormone-binding globulin (SHBG), whereas the levels of
corticoid binding globulin (CBG) and circulating cortisol are unaffected.
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.

4.5

Interaction with other medicinal products and other forms of interaction
Since Tibolone-Mithra may increase blood fibrinolytic activity, it may enhance the
effect of anticoagulants. This effect has been demonstrated with warfarin. Caution
should therefore be exercised during the simultaneous use of Tibolone-Mithra and
anticoagulants, especially when starting or stopping concurrent Tibolone-Mithra
treatment. If necessary, the dose of warfarin should be adjusted.

There is limited information regarding pharmacokinetic interactions with tibolone. An
in vivo study showed that simultaneous treatment of tibolone affects
pharmacokinetics of the cytochrome P450 3A4 substrate midazolam to a moderate
extent. Based on this, drug interactions with other CYP3A4 substrates might be
expected.
CYP3A4 inducing compounds such as barbiturates, carbamazepine, hydantoins and
rifampicin may enhance the metabolism of tibolone and thus affect its therapeutic
effect.
Herbal preparations containing St.John`s wort (Hypericum Perforatum) may induce
the metabolism of oestrogens and progestogens via CYP3A4. Clinically, an increased
metabolism of oestrogens and progestogens may lead to decreased effect and changes
in the uterine bleeding profile.

4.6

Fertility, pregnancy and lactation
Pregnancy
Tibolone-Mithra is contraindicated during pregnancy (see section 4.3). If pregnancy
occurs during medication with Tibolone-Mithra, treatment should be withdrawn
immediately. For Tibolone-Mithra no clinical data on exposed pregnancies are
available. Studies in animals have shown reproductive toxicity (see section 5.3). The
potential risk for humans is unknown.
Breastfeeding
Tibolone-Mithra is contraindicated during lactation (see section 4.3).
Fertility
In animal studies, Tibolone-Mithra had anti-fertility activities by virtue of its
hormonal properties.

4.7

Effects on ability to drive and use machines
Tibolone-Mithra is not known to have any effects on alertness and concentration.

4.8

Undesirable effects
This section describes undesirable effects, which were registered in 21 placebocontrolled studies (including the LIFT study), with 4079 women receiving therapeutic
doses (1.25 or 2.5 mg) of Tibolone-Mithra and 3476 women receiving placebo. The
duration of treatment in these studies ranged from 2 months to 4.5 years. Table 1
shows the undesirable effects that occurred statistically significantly more frequently
during treatment with Tibolone-Mithra than with placebo.
Table 1 Undesirable effects of Tibolone-Mithra

System Organ
Class

Metabolism
and nutrition
disorders
Gastrointestina
l disorders
Skin
and
subcutaneous
tissue disorders
Reproductive
system
and
breast
disorders

Common
(≥1/100
<1/10)

to

Lower
abdominal pain
Abnormal hair
growth
Vaginal
discharge
Endometrial
was thickening
Postmenopausa
l haemorrhage
Breast
tenderness
Genital pruritus
Vaginal
candidiasis
Vaginal
haemorrhage
Pelvic pain
Cervical
dysplasia
Genital
discharge
Vulvovaginitis

Uncommo
n
(≥1/1,000
to <1/100)
Oedema**

Abdominal
discomfort*
*
Acne

Rare
(≥1/10,00
0
to
<1/1,000)

Pruritus**

Breast
discomfort
Fungal
infection
Vaginal
mycosis
Nipple pain

Investigations

Weight
increase
Abnormal
cervical smear*
*The majority consisted of benign changes. Cervix pathology (cervical carcinoma)
was not increased with Tibolone-Mithra compared to placebo.
**These adverse reactions were identified through post-marketing surveillance. The
frequency category was estimated based on relevant clinical trials.
In market use, other undesirable effects that have been observed include: dizziness,
rash, seborrheic dermatosis, headache, migraine, visual disturbances (including
blurred vision), depression, effects on the musculoskeletal system such as arthralgia
or myalgia and changes in liver function parameters.
Breast cancer

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 and tibolone therapies is substantially
lower than 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 epidemiological study (Million Women Study) are presented.

Table 2 Million Women study – Estimated additional risk of breast cancer after
5 years’ use
Age range
Additional
cases Risk ratio (95% CI) Additional cases per
per
1000
never(*3)
1000 HRT users
(Years)
users of HRT over
over 5 years (95%
a 5 year period (*2)
CI)
Estrogen-only HRT
50-65
9-12
1.2
1-2 (0-3)
Combined estrogen-progestagen
50-65
9-12
1.7
6 (5-7)
Tibolone
50-65
9-12
1.3
3 (0-6)
*2: Taken from baseline incidence rates in developed countries
*3: Overall risk ratio. The risk ratio is not constant but will increase with increasing
duration of use
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 or tibolone.
The randomised placebo controlled trial that included women who had not been
screened for endometrial abnormalities at baseline, and therefore reflected clinical
practice, identified the highest risk of endometrial cancer (LIFT study, mean age 68
years). In this study, no cases of endometrial cancer were diagnosed in the placebo
group (n=1,773) after 2.9 years compared with 4 cases of endometrial cancer in the
Tibolone-Mithra group (n=1,746). This corresponds to a diagnosis of 0.8 additional
case of endometrial cancer in every 1000 women who used Tibolone-Mithra for one
year in this study (see section 4.4).
Ovarian cancer
Use of estrogen-only or combined estrogen-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.

In the Million Women Study, taking 5 years of tibolone resulted in 1 extra case per
2500 users (see section 4.4).
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 HRT (see section
4.4).
Results of the WHI studies are presented.
Table 3 WHI Studies - Additional risk of VTE over 5 years’ use
Age range (years)
Incidence per 1000 Risk ratio (95% CI)
women in placebo
arm
over 5 years
Oral estrogen-only (*4)
50-59
7
1.2 (0.6-2.4)
Oral combined estrogen-progesteron
50-59
4
2.3 (1.2–4.3)
*4: Study in women with no uterus

Additional cases
per 1000 HRT
users

1 (-3-10)
5 (1-13)

Risk of coronary artery disease
- The risk of coronary artery disease is slightly increased in users of combined
estrogen-progestogen HRT over the age of 60 (see section 4.4). There is no evidence
to suggest that the risk of myocardial infarction with tibolone is different to the risk
with other HRT.
Risk of ischaemic stroke
- The relative risk of ischaemic stroke is not dependent on age or on duration of
use, but as the baseline risk is strongly age-dependent, the overall risk of
ischaemic stroke in women who use HRT or tibolone will increase with age, see
section 4.4.
-

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.

-

A 2.9 year randomised controlled study has estimated a 2.2-fold increase in the
risk of stroke in women (mean age 68 years) who used 1.25 mg Tibolone-Mithra
(28/2249) compared with placebo (13/2257). The majority (80%) of strokes were
ischaemic.

The baseline risk of stroke is strongly age-dependent. Thus, the baseline incidence
over a 5 year period is estimated to be 3 per 1000 women aged 50-59 years and 11 per
1000 women aged 60-69 years.

-

For women who use Tibolone-Mithra for 5 years, the number of additional cases
would be expected to be about 4 per 1000 users aged 50-59 years and 13 per 1000
users aged 60-69 years.

Table 4 WHI Studies combined - Additional risk of ischaemic stroke over 5
years’ use
Risk ratio (95%CI)
Additional
Incidence per
Age range
(years)
1000 women in
cases per 1000
placebo arm
HRT users
over 5 years
over 5 years
50-59
8
1.3 (1.1-1.6)
3 (1-5)

Other adverse reactions have been reported in association with oestrogen/progestagen
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)
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 theYellow Card Scheme:
Website: www.mhra.gov.uk/yellowcard

4.9

Overdose
The acute toxicity of tibolone in animals is very low. Therefore, toxic symptoms are
not expected to occur, even when several tablets are taken simultaneously. In cases of
acute overdose, nausea, vomiting and vaginal bleeding in females may occur. No
specific antidote is known. Symptomatic treatment can be given if necessary.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: ATC code: G03CX01, other estrogens
Following oral administration, tibolone is rapidly metabolised into three
compounds, which all contribute to the pharmacodynamic profile of TiboloneMithra. Two of the metabolites (3α-OH-tibolone and 3β-OH-tibolone) have
oestrogenic-like activities, whereas the third metabolite (4Δ-isomer of
tibolone) has progestogenic and androgenic-like activities.

Tibolone-Mithra substitutes for the loss of oestrogen production in
postmenopausal women and alleviates menopausal symptoms. TiboloneMithra prevents bone loss following menopause or ovariectomy.
Clinical trial information of Tibolone-Mithra:
Relief of oestrogen-deficiency symptoms.
Relief of menopausal symptoms generally occurs during the first few weeks of
treatment.
Effects on the endometrium and bleeding patterns.
There have been reports of endometrial hyperplasia and endometrial cancer in
patients treated with Tibolone-Mithra (see section 4.4 and 4.8).
Amenorrhea has been reported in 88% of women using Tibolone-Mithra 2.5
mg after 12 months of treatment. Breakthrough bleeding and/or spotting has
been reported in 32.6% of women during the first 3 months of treatment, and
in 11.6% of women after 11-12 months of use.
Prevention of osteoporosis
Oestrogen deficiency at menopause is associated with an increasing bone
turnover and decline in bone mass. Protection appears to be effective for as
long as treatment is continued. After discontinuation of HRT, bone mass is lost
at a rate similar to that in untreated women.
In the LIFT study, Tibolone-Mithra reduced the number of women (mean age
68 years) with new vertebral fractures compared to placebo during the 3 years
of treatment (ITT: Tibolone-Mithra to placebo odds ratio 0.57; 95% CI [0.42,
0.78]).
After 2 years of treatment with Tibolone-Mithra (2.5 mg), the increase in
lumbar spine bone mineral density (BMD) was 2.6 3.8%. The percentage of
women who maintained or gained BMD in lumbar zone during treatment was
76%. A second study confirmed these results.
Tibolone-Mithra (2.5 mg) also had an effect on hip BMD. In one study, the
increase after 2 years was 0.7 3.9% at the femoral neck and 1.7 3.0% at the
total hip. The percentage of women who maintained or gained BMD in the hip
region during treatment was 72.5%. A second study showed that the increase
after 2 years was 1.3 5.1% at the femoral neck and 2.9 3.4% at the total
hip. The percentage of women who maintained or gained BMD in the hip
region during treatment was 84.7%.
Effects on the breast
In clinical studies mammographic density is not increased in women treated
with Tibolone-Mithra compared to placebo.

5.2

Pharmacokinetic properties
Absorption and biotransformation

Following oral administration, tibolone is rapidly and extensively absorbed. Due to
rapid metabolism, the plasma levels of tibolone are very low. The plasma levels of the
Δ4-isomer of tibolone are also very low. Therefore some of the pharmacokinetic
parameters could not be determined. Peak plasma levels of the 3α-OH and the 3β-OH
metabolites are higher but accumulation does not occur.
Table 5 Pharmacokinetic parameters of Tibolone-Mithra (2.5 mg)

Tibolone

3α-OH
metaboline
SD
MD

Δ 4 Isomer

3β-OH
metabolite
SD
MD

SD

MD

SD

MD

Cmax
(ng/ml)

1,37

1,72

14,23

14,15

3,43

3,75

0,47

0,43

Caverage

-

-

-

1,88

-

-

-

-

Tmax (h)

1,08

1,19

1,21

1,15

1,37

1,35

1,64

1,65

T1/2 (h)

-

-

5,78

7,71

5,87

-

-

-

-

-

-

0,23

-

-

-

-

-

-

52,23

44,73

16,23

9,20

-

-

Cmin
(ng/ml)
AUC 0-24
(ng/ml.h)

SD = single dose ; MD = multiple dose
Elimination
Excretion of tibolone is mainly in the form of conjugated (mostly sulfated)
metabolites. Part of the administered compound is excreted in the urine, but most is
eliminated via the faeces.
The consumption of food has no significant effects on the extent of absorption.
Other special populations
The pharmacokinetic parameters for tibolone and its metabolites were found to be
independent of renal function.

5.3

Preclinical safety data
In animal studies, tibolone had anti-fertility and embryotoxic activities by virtue of its
hormonal properties. Tibolone was not teratogenic in mice and rats. It displayed
teratogenic potential in the rabbit at near-abortive dosages (see section 4.6). Tibolone
is not genotoxic under in vivo conditions. Although a carcinogenic effect was seen in
certain strains of rat (hepatic tumours) and mouse (bladder tumours), the clinical
relevance of this is uncertain.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tibolone-Mithra contains:
- lactose monohydrate
- mannitol
- potato starch
- magnesium stearate
- ascorbyl palmitate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.

6.4

Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package, in order to protect from light and moisture.

6.5

Nature and contents of container
Push-trough pack of transparent PVC-Alu tablets pack sizes: cardboard boxes
containing 1, 3 or 6 blisters with 28 or 30 tablets.
Not all pack size may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Mithra Pharmaceuticals S.A
5, rue Saint-Georges
4000 Liege

Belgium

8

MARKETING AUTHORISATION NUMBER(S)
PL 34096/0010

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/03/2016

10

DATE OF REVISION OF THE TEXT
21/03/2016

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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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