The format of this leaflet was determined by the Ministry of Health and its content

was checked and approved by it on July 2012

1. NAME OF THE MEDICINAL PRODUCT

PROGYLUTON
Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Calendar-pack containing 11 white tablets of 2 mg estradiol valerate each, plus 10 light
brown tablets of 2 mg estradiol valerate and 0.5 mg norgestrel each.

3. PHARMACEUTICAL FORM
Coated tablets.

4. CLINICAL PARTICULARS
4.1 Therapeutic indication
Two phase preparation for climacteric and cycle disturbances.

4.2 Posology and method of administration

Proguluton is a cyclic HRT product. One tablet is to be taken orally once a day for 21
days, followed by a 7 day tablet free interval. Therefore each new pack is started after a 28
day cycle. The white tablets should be taken from days 1 to 11 followed by the brown
tablets from days 12 to 21. It is recommended that the tablets are taken at the same time
every day

For initiation and continuation of treatment of peri- and post-menopausal symptoms the
lowest effective dose for the shortest duration (see also Section 4.4) should be used.

For women still having periods, the first tablet should be taken on the 5th day of their
menstrual period. If menstruation has stopped, or is infrequent or sporadic, then the first
tablet can be taken any time

If the patient is being transferred from a continuous HRT product, the patient may start
Progyluton on any convenient day. For those transferring from a cyclic or sequential
product, Progylton should be started following completion of the previous regimen

If a tablet is missed, it should be taken as soon as possible, unless it is more than 12 hours
late. In this case the missed tablet should be left in the pack and the next tablet taken at the
right time. Missing a dose may result in breakthrough bleeding or spotting

Unless there is a previous diagnosis of endometriosis, it is not recommended that

progestagen-containing HRT be given to hysterectomised women

Children and adolescents

Progyluton is not indicated for use in children and adolescents

Geriatric patients
There are no data suggesting a need for dosage adjustment in women aged 65 years or
(older (see section 4.4 Special warnings and precautions for use

Patients with hepatic impairment

Progyluton has not been specifically studied in patients with hepatic impairment. (see 4.3
(Contraindications

Patients with renal impairment

Progyluton has not been specifically studied in renally impaired patients. Available data do
not suggest a need for dosage adjustment in this patient population.

4.3 Contraindications
Pregnancy and lactation
Undiagnosed vaginal bleeding
Known, past or suspected cancer of the breast
Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)
Untreated endometrial hyperplasia
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infraction)-
Previous or current venous thromboembolism (deep venous thrombosis, pulmonary
embolism)
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see
section 4.4)
Known hypersensitivity to any of the components of Progyluton
Acute liver disease or a history of liver disease unless liver function tests have returned to
normal
Porphyria

4.4 Special warnings and special 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 examination (including pelvic and breast) should be guided by
this and by the contraindications (section 4.3) and warnings for use (section 4.4). 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.

Before starting treatment, pregnancy should be excluded. If withdrawal bleeding fails to

occur at about 28-day intervals, the possibility of pregnancy should be considered in peri-
menopausal women.

The patient may experience blood loss after completing each pack.

Conditions that need supervision

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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
monitored. It should be taken into account that these conditions may recur or may be
aggravated during treatment with Progyluton, 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
chorea minor
a history of endometrial hyperplasia (see below)
epilepsy
asthma
otosclerosis
hereditary angioedema

Close medical supervision (including periodic measurement of prolactin levels) is

necessary if the patient suffers from prolactinoma.

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the
following situations:
significant increase in blood pressure
pregnancy
jaundice or deterioration in liver function.
migrainous headaches occur for the first time

Endometrial Hyperplasia
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 non-users, depending on the duration of treatment and oestrogen
dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10
years.

The addition of a progestagen for 10 days per cycle in non-hysterectomised women

reduces, but does not eliminate, this risk.

Breakthrough bleeding and spotting may occur during the first few months of treatment,
but if this occurs after some time on therapy, or continues after treatment has been
discontinued, the reason should be investigated. This may include an 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.

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

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

The excess risk becomes apparent within a few years of use but returns to baseline within a
few (at most five) years after stopping treatment.

HRT, especially oestrogen-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. 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 HRTs may confer a similar, or slightly smaller, risk (see section 4.8).

Venous Thromboembolism (VTE)

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 (section 4.8).

Patients with known thrombophilic states have an increased risk of VTE and HRT may add
to this risk. HRT is therefore contraindicated in these patients (see section 4.3).

Generally recognised risk factors for VTE include use of oestrogens, older age, major
surgery, prolonged immobilisation, obesity (BMI >30kg/m2) pregnancy/postpartum
period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the
possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures need to be considered to prevent

VTE following surgery. If prolonged immobilisation is to follow elective surgery
temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be
restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of
thrombosis at a young age, screening may be offered after careful counselling regarding its
limitations (only a proportion of thrombophilic defects are identified by screening).

If a thrombophilic defect is identified which segregates with thrombosis in family

members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies
or a combination of defects) HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the

benefit-risk of use of HRT
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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 leg, sudden pain in chest, dyspnoea)

Coronary Arterial 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-
progestagen or oestrogen only HRT.

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen+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+progestagen use is very low in healthy women
close to menopause, but will rise with more advanced age.

Oestrogen-only
Randomised controlled data found no increased risk of CAD in hysterectomised women
using oestrogen-only therapy.

Ischaemic Stroke
Combined oestrogen-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).

Liver tumor
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 intra-abdominal hemorrhage. A hepatic tumor
should be considered in the differential diagnosis if upper abdominal pain, enlarged liver,
or signs of intra-abdominal hemorrhage occur.

Other Conditions
Oestrogens 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 of Progyluton may increase.

Women with pre-existing hypertriglyceridemia should be followed closely during

oestrogen replacement or hormone replacement therapy, since rare cases of large increases
of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in
this condition.

Oestrogens increase thyroid binding globulin (TBG) leading to increased circulating total
thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by
radio-immunoassay), or T3 levels (by radio-immunoassay). T3 resin uptake is decreased
reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other
binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-
hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex
steroids, respectively. Free or biological active hormone concentrations are unchanged.
Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-
antitrypsin, ceruloplasmin).
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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.

Progyluton cannot be used as a contraceptive.

Hormonal contraception should be stopped when treatment with Progyluton is started and
the patient should be advised to take non-hormonal contraceptive precautions.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate

symptoms of angioedema.

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

4.5 Interaction with other medicinal and other forms of interaction

The metabolism of oestrogens and progestagens may be increased by concomitant use of
substances known to induce drug-metabolising enzymes, specifically cytochrome P450
enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), and anti-
.(infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing
properties when used concomitantly with steroid hormones. Herbal preparations
containing St John's Wort (Hypericum Perforatum) may induce the metabolism of
.oestrogens and progestagens

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased

efficacy and changes in uterine bleeding profile

The requirement for oral antidiabetics or insulin can change.

4.6 Pregnancy and lactation

Progyluton is not indicated for use during pregnancy or lactation. If pregnancy occurs
during medication with Progyluton, treatment should be discontinued immediately.
No data on exposed pregnancies are available. Studies in animals have not shown
reproductive toxicity.

The results of most epidemiological studies to-date, relevant to inadvertent foetal exposure
to combinations of oestrogens and progestagens indicate no teratogenic or foetotoxic
effect.

4.7 Effects on ability to drive and use machines

No observed effects.

4.8 Undesirable effects

During the first few months treatment, breakthrough bleeding, spotting and breast
tenderness or enlargement can occur. These are usually temporary and normally disappear
after continued treatment.

System Organ Class Common Uncommon Rare

≥1/100, <1/10 ≥1/1,000, <1/100 ≥1/10,000 < 1/1,000
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MedDRA v. 8.0

Immune system Hypersensitivity

disorders reaction
Metabolism and Weight increase or
nutrition disorders weight decrease
Psychiatric Depressed mood Anxiety,
disorders libido decreased or
libido increased
Nervous system Headache Dizziness Migraine
disorders
Eye disorders Visual disturbances Contact lens
intolerance
Cardiac disorders Palpitations
Gastrointestinal Abdominal pain, Dyspepsia Bloating, vomiting
disorders nausea
Skin and Rash, pruritus Erythema nodosum, Hirsutism, acne
subcutaneous tissue urticaria
disorders
Musculoskeletal Muscle cramps
and subcutaneous
tissue disorders
Reproductive Uterine/vaginal Breast pain, breast Dysmenorrhea,
system and breast bleeding including tenderness vaginal discharge,
disorders spotting (bleeding premenstrual-like
irregularities usually syndrome, breast
subside during enlargement
continued treatment)
General disorders Edema Fatigue
and administration
site conditions
The most appropriate MedDRA term (version 8.0) to describe a certain reaction is listed.
Synonyms or related conditions are not listed, but should be taken into account as well.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate

symptoms of angioedema (see section Special Warnings and special precautions for use).

Other reactions have also been reported in association with oestrogen/progestagen

treatment:
- Oestrogen-dependent neoplasms benign and malignant, e.g. breast* (see
below) and endometrial** (see below) cancer
- Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and
pulmonary embolism, is more frequent among hormone replacement therapy
users than among non-users. For further information, see section 4.3
Contraindications and 4.4 Special warnings and precautions for use
- Myocardial infarction and stroke
- Gall bladder disease
- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema
nodosum, vascular purpura
- Probable dementia (see Section 4.4)

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 - In women with hereditary angioedema exogenous estrogens may induce or
exacerbate symptoms of angioedema.

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 oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data
from 51 epidemiological studies (in which >80% of HRT use was oestrogen-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 oestrogen plus progestagen combined HRT, several epidemiological studies have
reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-
progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00,
95%CI: 1.88 – 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use
of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of
oestrogen-progestagen 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 oestrogen-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 oestrogen plus progestagen 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 oestrogen-
progestagen 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 oestrogen + progestagen combined HRT (CEE +
MPA), the number of additional cases would be
between 0 and 9 (best estimate = 4) for 5 years’ use.

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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 oestrogens. 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 oestrogen dose, the
reported increase in endometrial cancer risk among unopposed oestrogen users varies from
2-to 12-fold greater compared with non-users. Adding a progestagen to oestrogen-only
therapy greatly reduces this increased risk.

4.9 Overdose
There have been no reports of ill-effects from overdosage. There are no specific antidotes,
and therefore treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
The estrogen in Progyluton is estradiol valerate, a prodrug of the natural
human 17ß- estradiol. Synthetic 17 β-estradiol, is chemically and
biologically identical to endogenous human estradiol. It substitutes for the
loss of oestrogen production in menopausal women, and alleviates
menopausal symptoms.

Oestrogens prevent bone loss following menopause or Ovariectomy.

The constituent norgestrel is a synthetic progestogen.

As oestrogens promote the growth of the endometrium, unopposed oestrogen increase the
risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces
the oestrogen induced risk of endometrial hyperplasia in non-hysterectomised women.

With the composition and the sequential regimen of Progyluton, including an estrogen
monophase for 11 days, an estrogen-progestogen combination for 10 days and a treatment-
free interval of 7 days, a menstrual cycle is established in women with an intact uterus,
provided the preparation is taken regularly.

Hormone replacement therapy (HRT) alleviates many of the symptoms of estradiol

deficiency in menopausal woman such as hot flushes, excessive sweating, urogenital
atrophy with symptoms of vaginal dryness and dyspareunia. .

Relief of menopausal symptoms was achieved by the third cycle after initiation of
treatment. In a clinical trial 314 subjects were enrolled and treated with 2 mg EV/0.5 mg
NG, 235 subjects completed the study. 93.3% of the subjects who completed showed a
reduction of the mean number of hot flushes per week of at least 50% after 3 cycles of
treatment. 61.1% of subjects had no hot flushes any more at cycle 3. In another clinical
trial one third of the subjects was free of vasomotor symptoms after one treatment cycle.

The Kupperman Index, related to the most common menopausal complaints which are
weighted according to their importance, significantly decreased from baseline at cycle 3.

9
Data from clinical trials indicate that regular monthly withdrawal bleeding occurred in
approximately 90% of women. The mean duration of withdrawal bleeding was 3.8 days.
Withdrawal bleeding starts on average 3.1 days after the last pill of the progestagen phase.
The amenorrhea rate (no bleeding or spotting) is less than 5%.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and

decline in bone mass.

The effect of oestrogens on the bone mineral density is dose-dependent. 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.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT,
alone or in combination with a progestagen – 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.

5.2 Pharmacokinetic properties

Estradiol valerate
Absorption
Estradiol valerate is rapidly and completely absorbed. The steroid ester is cleaved into
estradiol and valeric acid during absorption and the first liver passage. At the same time,
estradiol undergoes extensive further metabolism, e.g. into estrone, estriol and estrone
sulfate. Only about 3 % of estradiol becomes bioavailable after oral administration of
estradiol valerate. Food does not affect the bioavailability of estradiol.

Distribution
Following single administration of 2mg estradiol valerate, maximum concentrations of
estradiol in serum of approx. 25-30 pg/ml are generally reached between 4-9 hours after
tablet intake. Within 24 hours after tablet intake, serum levels of estradiol declined to
concentrations of about 15 pg/ml. Estradiol binds to albumin and the sex hormone binding
globulin (SHBG). However, the binding to SHBG is lower than that of levonorgestrel. The
unbound fraction of estradiol in serum is about 1-1.5 % and the SHBG- bound fraction is
in the range of 30-40 %.
The apparent volume of distribution of estradiol after single intravenous administration is
about 1 l/kg.

Metabolism
After the ester cleavage of the exogenously administered estradiol valerate, the
metabolism of the drug follows the biotransformation pathways of endogenous estradiol.
Estradiol is mainly metabolized in the liver but also extrahepatically e.g. in gut, kidney,
skeletalmuscles and target organs. These processes involve the formation of estrone,
estriol, catecholestrogens and sulfate and glucuronide conjugates of these compounds,
which are all distinctly less estrogenic or even nonestrogenic.

Elimination
The total serum clearance of estradiol following single intravenous administration, shows
high variability in the range of 10-30 ml/min/kg. A certain proportion of estradiol
metabolites are excreted in the bile and undergo a so-called enterohepatic circulation.
Ultimately estradiol metabolites are mainly excreted as sulfates and glucuronides with the
urine.

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Steady state conditions
In relation to the single dose, approximately two times higher serum levels of estradiol are
observed after multiple administration. On average, the concentration of estradiol varies
between 30 (minimum levels) and 60 pg/ml (maximum levels). Estrone, as a less
estrogenic metabolite, reaches about 8-times higher concentrations in serum, estrone
sulfate reaches approximately 150-times higher concentrations. After stopping the
treatment with
Progyluton, pre-treatment levels of estradiol and estrone are reached within 2-3 days. No
distinct difference in the estrogen levels is observed between the treatment phase with
estradiol valerate alone or in combination with norgestrel.

Norgestrel
Absorption
After oral administration, norgestrel is absorbed rapidly and completely. The active
component of the racemate norgestrel is levonorgestrel which becomes completely
bioavailable from the racemate and accounts for about half of the dose of norgestrel.

Distribution
On an average, maximum concentrations of levonorgestrel in serum of 7-8 ng/ml are
already reached within 1-1.5 hours after a single administration of Progyluton.
Subsequently, serum levels of levonorgestrel decline biphasically with a mean terminal
half-life of 27 hours and reach minimum concentrations of about 1 ng/ml 24 hours post
dose.

Levonorgestrel binds to albumin and SHBG. Only about 1-1.5 % of the total levonorgestrel
concentration in serum is not protein-bound. The relative fractions of free, albumin- and
SHBG- bound levonorgestrel are strongly dependent on the concentration of SHBG in
serum. After induction of the binding proteins, the fraction bound to SHBG increases
whereas the unbound
fraction and that bound to albumin decreases. At the end of the estrogen monophase of the
Progyluton treatment cycle, the concentration of SHBG reaches the highest levels in serum
which then decreases to the lowest levels at the end of the combination phase.
Accordingly, the free fraction of levonorgestrel amounts to about 1 % at the beginning and
about 1.5 % at the end of the combination phase. The corresponding fractions of
levonorgestrel bound to SHBG are 70 and 65 %, respectively.

Biotransformation
Norgestrel is completely metabolized. Biotransformation of the active substance
levonorgestrel follows the known pathways of steroid metabolism. Pharmacologically
active metabolites are not known.

Elimination
The total clearance rate of levonorgestrel from serum is 1 ml/min/kg.
With a half-life of about 1 day, approximately the same proportions of the metabolites of
norgestrel are excreted with the urine and the bile.

Steady-state conditions
Based on the elimination half-life of levonorgestrel in serum of about 24 hours, an
accumulation of the active substance in serum would be expected. Accordingly, elevated
trough levels ofabout 1 ng/ml are observable after repeated administration. However, due
to the simultaneous change in the protein binding capacity during treatment (decrease in
SHBG concentration), the area under the serum levels-time course of levonorgestrel does
not really differ between the beginning and the end of the 10-day treatment phase with the
11
estrogen/progestogen combination. Thus, no accumulation of levonorgestrel in serum is
observed after multiple administration of Progyluton.

5.3 Preclinical safety data

None

6 PHARMACEUTICAL PARTICULARS
6.1 list of exicipients
Lactose monohydrate, maize starch, polyvidone 25000, talc, magnesium stearate, sucrose,
polyvidone 700000, macrogol 6000, calcium carbonate, glycerol 85%, titanium dioxide
(E171), ferric oxide yellow (E172), ferric oxide red (E172) , montanglycol wax

6.2 Incompatabilitis
None known

6.3 Shelf life

5 years

6.4 Special precautions for storage

Do not store above 25C.

6.5 Nature and contents of container

Each pack consists of aluminium foil and PVC and contains 21 tablets.

6.6 Instructions for use and handling (and disposal)

No special requirements for disposal.

MANUFACTURER:
Bayer Weimar GmBH und Co. KG, Weimar, Germany

REGISTRATION HOLDER:
Bayer Israel Ltd., 36 Hacharash St., Hod Hasharon 45240

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