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GEDAREL 20/150 MICROGRAM FILM-COATED TABLETS

Active substance(s): DESOGESTREL / ETHINYLESTRADIOL

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Transcript
SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Gedarel 20/150 microgram film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 micrograms ethinylestradiol and 150 micrograms
desogestrel
Excipient with known effect: 64.3 mg lactose (as lactose monohydrate).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet
Slightly yellow, round shaped, biconvex film-coated tablets of about 6 mm diameter,
with P9 sign on one side and RG sign on other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Oral contraception
The decision to prescribe Gedarel should take into consideration the individual
woman’s current risk factors, particularly those for venous thromboembolism (VTE),
and how the risk of VTE with Gedarel compares with other combined hormonal
contraceptives (CHCs) (see sections 4.3 and 4.4).
4.2

Posology and method of administration

Posology
How to take Gedarel
The tablets should be taken in the order of succession stated on the package every day
at about the same time of the day. One tablet is taken daily for 21 consecutive days.

Each subsequent pack is started after a 7-day tablet-free interval; during this tabletfree interval a menstruation- like withdrawal bleeding occurs. This bleeding usually
begins on the 2nd or 3rd day after ingestion of the last tablet and it may not have
ceased, before the next pack is started.
How to start Gedarel
No preceding intake of COCs (within the last month)
The tablet intake should be started on day 1 of the normal menstrual cycle (i.e. on the
first day on which the woman has a menstrual bleeding). Tablet intake is also allowed
to start on day 2-5, but during the first cycle concurrent use of a barrier method for the
first 7 days of tablet intake is advisable.
Changing from another combined hormonal contraceptive (combined oral
contraceptive (COC), combined contraceptive vaginal ring or transdermal patch)
The woman should start taking Gedarel preferably on the day after the last active
tablet (the last tablet containing the active substance) of her previous COC, but at the
latest on the day following the usual tablet-free interval or following the last placebo
tablet of her previous COC.
In case a vaginal ring or a transdermal patch has been used, the woman should start
using Gedarel preferably on the day of removal, but at the latest when the next
application would have been due.
If the woman has been using her previous method consistently and correctly and if it
is reasonably certain that she is not pregnant she may also switch from her previous
COC on any day of the cycle.
Changing from progestogen only products (progetogen-only-pills, injection, implant)
or from a progestogen-releasing intrauterine system (IUS)
The woman can change from progestogen-only pills on any day (changing from
implant or IUS on the day of its removal; changing from injection when the next
injection should have been given) but should in all of these cases be advised to
additionally use a barrier method for the first 7 days of tablet-taking.
After abortion in the 1st trimester
Tablet intake should start immediately. In this case no further contraceptive measures
are necessary.
After delivery or abortion in the 2nd trimester
For breast-feeding women - see section 4.6.
The woman should be advised to start the pill on day 21-28 after delivery or abortion
in the 2nd trimester. She should be advised to use a barrier method concurrently
during the first 7 days of tablet intake if she starts the pill later. In case she has already
had intercourse, pregnancy should be excluded before she starts tablet intake, or she
should wait for her first menstrual bleeding.
Forgotten tablets

If the tablet intake is forgotten for less than 12 hours, contraceptive protection is not
reduced. The woman should take the forgotten tablet as soon as she remembers, and
the remaining tablets are taken as usual.
If the tablet intake is forgotten for more than 12 hours, contraceptive protection may
be reduced. The following two basic rules should be considered in case of forgotten
tablets:
1.
Continuous tablet intake must not be interrupted for longer than a period of 7
days.
2.
7 days of uninterrupted tablet intake are required to achieve sufficient
suppression of the hypothalamus-pituitary-ovarian-axis.
Thus, the following advice may be given for daily practice:
Week 1
The user should take the last forgotten tablet as soon as she remembers, even if this
means that she has to take 2 tablets at the same time. Then, she continues taking the
tablets at the usual time of the day. She should concurrently use a barrier method, e.g.
a condom, for the next 7 days. If intercourse has taken place during the preceding 7
days, the possibility of pregnancy should be considered. The more tablets are
forgotten and the closer they are to the regular tablet-free period, the higher the risk of
pregnancy is.
Week 2
The user should take the last forgotten tablet as soon as she remembers, even if this
means that she has to take 2 tablets at the same time. Then, she continues taking the
tablets at the usual time of the day. Provided that the tablets have been taken in a
correct manner during the 7 days preceding the forgotten tablet, it is not necessary to
take further contraceptive measures. However, if this is not the case, or if more than 1
tablet has been forgotten, the woman should be advised to use another contraceptive
method for 7 days.
Week 3
The risk of reduced contraceptive protection is imminent due to the next tablet-free
period. However, this risk may be prevented by adjusting tablet intake. Thus, it is not
necessary to take further contraceptive measures if one of the two alternatives below
is followed, provided that all tablets have been taken in a correct manner during the 7
days preceding the forgotten tablet. If this is not the case, the woman should be
advised to follow the first of the two alternatives and concurrently use another
contraceptive method for the next 7 days.
1.
The user should take the last forgotten tablet as soon as she remembers even if
it means that she has to take 2 tablets at the same time. Then she continues taking the
tablets at the usual time of the day. She will begin taking the next pack immediately
after taking the last tablet in the present pack, i.e. there is no break between the packs.
It is not very likely that the user will have her menstrual bleeding until the end of the
second pack, but she may experience spotting or break-through bleeding on the days
she is taking tablets.

2.
The woman may also be advised to stop taking tablets from the present pack.
In that case she should keep a tablet-free period of up to 7 days, including those days
when she forgot tablets, and then continue with the next pack.
In case the woman has forgotten tablets and then does not have her menstrual
bleeding in the first normal tablet-free period, the possibility of pregnancy should be
considered
Precautions in case of vomiting or severe diarrhoea
If vomiting or severe diarrhoea occur within 3-4 hours after tablet intake, the tablet
may not be absorbed completely. Therefore, the precautions concerning forgotten
tablets as described in section “Forgotten tablets” 4.2. apply. If the woman does not
want to change her usual tablet intake, she has to take the necessary extra tablet(s)
from another pack.
How to postpone a withdrawal bleed
Postponing the monthly withdrawal bleed is not an indication of this product. To
delay a period the woman should continue with another blister pack of Gedarel
without a tablet-free interval. The extension can be carried on for as long as wished
until the end of the second pack. During the extension the woman may experience
breakthrough-bleeding or spotting. Regular intake of Gedarel is then resumed after the
usual 7-day tablet-free interval
To shift her periods to another day of the week than the woman is used to with her
current scheme, she can be advised to shorten her forthcoming tablet-free interval by
as many days as she likes. The shorter the interval, the higher the risk that she does
not have a withdrawal bleed and will experience breakthrough-bleeding and spotting
during the subsequent pack (just as when delaying a period).
Paediatric population
The safety and efficacy of desogestrel in adolescents below 18 years has not yet been
established. No data are available.
Method of administration
For oral administration.
4.3

Contraindications

Combined hormonal contraceptives (CHCs) should not be used in the following
conditions.
Should any of the condition appear for the first time during COCs use, the product
should be stopped immediately.
- Presence or risk of venous thromboembolism (VTE)
o Venous thromboembolism – current VTE (on anticoagulants) or history of
(e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]).
o Known hereditary or acquired predisposition for venous
thromboembolism, such as APC-resistance, (including Factor V Leiden),
antithrombin-III-deficiency, protein C deficiency, protein S deficiency.
o Major surgery with prolonged immobilisation (see section 4.4).

-

-

4.4

o A high risk of venous thromboembolism due to the presence of multiple
risk factors (see section 4.4).
Presence or risk of arterial thromboembolism (ATE)
o Arterial thromboembolism – current arterial thromboembolism, history of
arterial thromboembolism (e.g. myocardial infarction) or prodromal
condition (e.g. angina pectoris).
o Cerebrovascular disease – current stroke, history of stroke or prodromal
condition (e.g. transient ischaemic attack, TIA).
o Known hereditary or acquired predisposition for arterial
thromboembolism, such as hyperhomocysteinaemia and antiphospholipidantibodies (anticardiolipin-antibodies, lupus anticoagulant).
o History of migraine with focal neurological symptoms.
o A high risk of arterial thromboembolism due to multiple risk factors (see
section 4.4) or to the presence of one serious risk factor such as:
• diabetes mellitus with vascular symptoms
• severe hypertension
• severe dyslipoproteinaemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.
Presence or history of severe hepatic disease as long as liver function values
have not returned to normal.
Presence or history of liver tumours (benign or malignant).
Known or suspected sex steroid-influenced malignancies (e.g. of the genital
organs or the breasts)
Endometrial hyperplasia.
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Hypersensitivity to the active substances or to any of the excipients listed in
section 6.1.
Special warnings and precautions for use

Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of
Gedarel should be discussed with the woman.
In the event of aggravation, or first appearance of any of these conditions or risk
factors, the woman should be advised to contact her doctor to determine whether the
use of Gedarel should be discontinued.
Circulatory disorders
Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) increases the risk of venous
thromboembolism (VTE) compared with no use. Products that contain
levonorgestrel, norgestimate or norethisterone are associated with the lowest risk
of VTE. Other products such as Gedarel may have up to twice this level of risk.
The decision to use any product other than one with the lowest VTE risk should
be taken only after a discussion with the woman to ensure she understands the

risk of VTE with Gedarel, how her current risk factors influence this risk, and
that her VTE risk is highest in the first ever year of use. There is also some
evidence that the risk is increased when a CHC is re-started after a break in use
of 4 weeks or more.
In women who do not use a CHC and are not pregnant about 2 out of 10,000 will
develop a VTE over the period of one year. However, in any individual woman the
risk may be far higher, depending on her underlying risk factors (see below).
It is estimated1 that out of 10,000 women who use a CHC containing desogestrel
between 9 and 12 women will develop a VTE in one year; this compares with about
62 in women who use a levonorgestrel-containing CHC.
In both cases, the number of VTEs per year is fewer than the number expected during
pregnancy or in the postpartum period.
VTE may be fatal in 1-2% of cases.
Number of VTE events per 10,000 women in one year
Number of
VTE
14 events

12

10

8

6

4

2

0

Non-CHCuser (2 events)

Levonorgestrel-containing CHC(5-7
events)

Desogestrel-containing CHC(9-12
events)

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood
vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.
Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may increase
substantially in a woman with additional risk factors, particularly if there are multiple
risk factors (see table).
Gedarel is contraindicated if a woman has multiple risk factors that put her at high
risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor,
1

These incidences were estimated from the totality of the epidemiological study data, using relative
risks for the different products compared with levonorgestrel-containing CHCs. 2 Mid-point of range of
5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of
approximately 2.3 to 3.6.

it is possible that the increase in risk is greater than the sum of the individual factors –
in this case her total risk of VTE should be considered. If the balance of benefits and
risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for VTE
Risk factor
Obesity (body mass index over 30
kg/m²).
Prolonged immobilisation, major
surgery, any surgery to the legs or
pelvis, neurosurgery, or major
trauma.

Note: temporary immobilisation
including air travel >4 hours can
also be a risk factor for VTE,
particularly in women with other
risk factors.
Positive family history (venous
thromboembolism ever in a sibling
or parent especially at a relatively
early age e.g. before 50).
Other medical conditions
associated with VTE.

Increasing age.

Comment
Risk increases substantially as BMI rises.
Particularly important to consider if other risk
factors also present.
In these situations it is advisable to discontinue
use of the pill (in the case of elective surgery at
least four weeks in advance) and not resume
until two weeks after complete remobilisation.
Another method of contraception should be used
to avoid unintentional pregnancy.
Antithrombotic treatment should be considered
if Gedarel has not been discontinued in advance.

If a hereditary predisposition is suspected, the
woman should be referred to a specialist for
advice before deciding about any CHC use.
Cancer, systemic lupus erythematosus,
haemolytic uraemic syndrome, chronic
inflammatory bowel disease (Crohn’s disease or
ulcerative colitis) and sickle cell disease.
Particularly above 35 years.

There is no consensus about the possible role of varicose veins and superficial
thrombophlebitis in the onset or progression of venous thrombosis.
The increased risk of thromboembolism in pregnancy, and particularly the 6 week
period of the puerperium, must be considered (for information on “Pregnancy and
lactation” see section 4.6).
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)
In the event of symptoms women should be advised to seek urgent medical attention
and to inform the healthcare professional that she is taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include:
- unilateral swelling of the leg and/or foot or along a vein in the leg;
- pain or tenderness in the leg which may be felt only when standing or
walking;
- increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of pulmonary embolism (PE) can include:
- sudden onset of unexplained shortness of breath or rapid breathing;
- sudden coughing which may be associated with haemoptysis;

- sharp chest pain;
- severe light headedness or dizziness;
- rapid or irregular heartbeat.
Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and
might be misinterpreted as more common or less severe events (e.g. respiratory tract
infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue
discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision
which can progress to loss of vision. Sometimes loss of vision can occur almost
immediately.
Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs with an increased risk for
arterial thromboembolism (myocardial infarction) or for cerebrovascular accident
(e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.
Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular accident in
CHC users increases in women with risk factors (see table). Gedarel is contraindicated
if a woman has one serious or multiple risk factors for ATE that puts her at high risk
of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is
possible that the increase in risk is greater than the sum of the individual factors - in
this case her total risk should be considered. If the balance of benefits and risks is
considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for ATE
Risk factor
Increasing age.
Smoking.

Hypertension.
Obesity (body mass index over 30
kg/m2).

Comment
Particularly above 35 years.
Women should be advised not to smoke if they
wish to use a CHC. Women over 35 who
continue to smoke should be strongly advised to
use a different method of contraception.
Risk increases substantially as BMI increases.
Particularly important in women with additional
risk. factors.
If a hereditary predisposition is suspected, the
woman should be referred to a specialist for
advice before deciding about any CHC use.

Positive family history (arterial
thromboembolism ever in a
sibling or parent especially at
relatively early age e.g. below 50).
Migraine.
An increase in frequency or severity of migraine
during CHC use (which may be prodromal of a
cerebrovascular event) may be a reason for
immediate discontinuation.
Other medical conditions
Diabetes mellitus, hyperhomocysteinaemia,
associated with adverse vascular
valvular heart disease and atrial fibrillation,
events.
dyslipoproteinaemia and systemic lupus
erythematosus.

Symptoms of ATE
In the event of symptoms women should be advised to seek urgent medical attention
and to inform the healthcare professional that she is taking a CHC.
Symptoms of a cerebrovascular accident can include:
- sudden numbness or weakness of the face, arm or leg, especially on one side
of the body;
- sudden trouble walking, dizziness, loss of balance or coordination;
- sudden confusion, trouble speaking or understanding;
- sudden trouble seeing in one or both eyes;
- sudden, severe or prolonged headache with no known cause;
- loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in
the chest, arm, or below the breastbone;
- discomfort radiating to the back, jaw, throat, arm, stomach;
- feeling of being full, having indigestion or choking;
- sweating, nausea, vomiting or dizziness;
- extreme weakness, anxiety, or shortness of breath;
- rapid or irregular heartbeats.
Occurrence of one or more of these symptoms may be a reason for immediate
discontinuation of Gedarel usage.
When considering risk/benefit, the physician should take into account that adequate
treatment of a condition may reduce the associated risk of thrombosis and that the risk
associated with pregnancy is higher than that associated with CHC use.
Tumours
Epidemiological studies indicate that the long-term use of COCs displays a risk factor
for the development of cervical cancer in women infected with human papillomavirus
(HPV). However, there is still uncertainty about the extent to which this finding may
be influenced by confounding effects (e.g. differences in number of sexual partners or
in use of barrier contraceptives).
A meta-analysis from 54 epidemiological studies reported that there is a slightly
increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who
are currently using COCs. The excess risk gradually disappears during the course of
the 10 years after cessation of COC use. Because breast cancer is rare in women under
40 years of age, the excess number of breast cancer diagnoses in current and recent
COC users is small in relation to the overall risk of breast cancer. These studies do not
provide evidence for causation. The observed pattern of increased risk may be due to
an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a
combination of both. The breast cancers diagnosed in ever-users tend to be less
advanced clinically than the cancers diagnosed in never-users.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours
have been reported in users of COCs. In isolated cases, these tumours have led to lifethreatening intra-abdominal haemorrhages. A hepatic tumour should be considered in

the differential diagnosis when severe upper abdominal pain, liver enlargement or
signs of intra-abdominal haemorrhage occur in women taking COCs.
Other conditions
Women with hypertriglyceridaemia or a family history thereof, may be at an increased
risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking
COCs, clinically relevant increases are rare. Relationship between COC use and
clinical hypertension has not been established. However, if a sustained clinically
significant hypertension develops during the use of a COC then it is prudent for the
physician to withdraw the COC and treat the hypertension. Where considered
appropriate, COC use may be resumed if normotensive values can be achieved with
antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both
pregnancy and COC use, but the evidence of an association with COC use is
inconclusive: Jaundice and/or itching in connection with cholestasis; gallstone
formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome;
Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss; (hereditary)
angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of
COC use until markers of liver function return to normal. Recurrent of cholestatic
jaundice which occurred first during pregnancy or previous use of sex steroids
necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose
tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics
using COCs. However, diabetic women should be carefully observed while taking
COCs.
Crohn’s disease and ulcerative colitis and worsening of endogenous depression and
epilepsy have been associated with COC use.
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 COCs.
Gedarel contains <65 mg lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should
not take this medicine.
When counselling the choice of contraceptive method(s), all the above information
should be taken into account.
Medical examination/consultation
Prior to the initiation or reinstitution of Gedarel a complete medical history (including
family history) should be taken and pregnancy must be ruled out. Blood pressure
should be measured and a physical examination should be performed, guided by the
contra-indications (see section 4.3) and warnings (see section 4.4). It is important to

draw a woman’s attention to the information on venous and arterial thrombosis,
including the risk of Gedarel compared with other CHCs, the symptoms of VTE and
ATE, the known risk factors and what to do in the event of a suspected thrombosis.
The woman should also be instructed to carefully read the user leaflet and to adhere to
the advice given. The frequency and nature of examinations should be based on
established practice guidelines and be adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against HIV
infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy
The efficacy of COCs may be reduced in the event of e.g., missed tablets (section
4.2), gastro-intestinal disturbances (section 4.2) or concomitant medication (section
4.5).
Herbal preparations containing St. John's wort (Hypericum perforatum) should not be
used while taking Gedarel due to the risk of decreased plasma concentrations and
reduced clinical effects of Gedarel (see section 4.5).
Reduced cycle control
With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur,
especially during the first months of use. Therefore, the evaluation of any irregular
bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, then nonhormonal causes should be considered and adequate, diagnostic measures are
indicated to exclude malignancy or pregnancy. These may include curettage.
In some women withdrawal bleeding may not occur during the tablet-free interval. If
the COC has been taken according to the directions described in section 4.2, it is
unlikely that the woman is pregnant. However, if the COC has not been taken
according to these directions prior to the first missed withdrawal bleed or if two
withdrawal bleeds are missed, pregnancy must be ruled out before COC use is
continued.
4.5

Interaction with other medicinal products and other forms of interaction

Interactions
Interactions between COCs and other drugs may lead to breakthrough bleeding and/or
COC failure. The following interactions have been reported in the literature:
Hepatic metabolism: interactions can occur with drugs that induce microsomal
enzymes, which can result in increased clearance of sex hormones (e.g., phenytoin,
hydantoins, barbiturates, primidone, bosentan, carbamazepine, rifampicin, rifabutin,
and possibly also oxcarbazepine, modafinil, topiramate, felbamate, griseofulvin,
ritonavir, and products containing St. John’s wort). Also HIV protease inhibitors with
an inducing potential (e.g., ritonavir and nelfinavir) and non-nucleoside reverse
transcriptase inhibitors (e.g., nevirapine and efavirenz), may affect hepatic
metabolism. Maximal enzyme induction is generally not seen for 2-3 weeks but may
then be sustained for at least 4 weeks after the cessation of drug therapy.

Contraceptive failures have also been reported with antibiotics, such as ampicillin and
tetracyclines. The mechanism of this effect has not been elucidated.
Women on treatment with any of these drugs should temporarily use a barrier method
in addition to the COC, or choose another method of contraception.
With microsomal enzyme-inducing drugs, the barrier method should be used during
the time of concomitant drug administration and for 28 days after their
discontinuation. In case of long-term treatment with microsomal enzyme inducing
drugs another method of contraception should be considered.
Women on treatment with antibiotics (except rifampicin and griseofulvin, which also
act as microsomal enzyme-inducing drugs) should use the barrier method until 7 days
after discontinuation. If the period during which the barrier method is used runs
beyond the end of the tablets in the COC pack, the next COC pack should be started
without the usual tablet free interval.
Women on short term treatment (up to one week) with some of the above mentioned
groups of drugs or individual drugs should temporarily use a barrier method
concomitantly with the COCs, i.e. in the period of other concomitant drug intake and
for 7 days after cessation of this drug. Women taking microsomal enzyme-inducing
drugs (e.g. rifampicin) should use a barrier method concomitantly with intake of
COCs for the period in which she is treated with rifampicin and for 28 days after
cessation of rifampicin. In case other concomitant drug intake exceeds the number of
tablets in the COCs pack, she should start the next pack of pills without keeping the
usual tablet-free period.
It is recommended by experts to increase the contraceptive steroid dosage for women
who are on long-term treatment with liver enzyme inducing drugs. If a high
contraceptive dosage is not advisable or this high dosage turns out to be insufficient or
unsafe, e.g. in case of irregular bleeding, another contraceptive method should be
advised.
The herbal preparation St.John’s wort (Hypericum perforatum) should not be taken
concomitantly with this medicine as this could potentially lead to a loss of
contraceptive effect. Break-through bleeding and unintended pregnancies have been
reported. This is due to induction of drug metabolising enzymes by St.John’s wort.
The inducing effect may persist for at least 2 weeks after cessation of treatment with
St.John’s wort.
Concomitant administration of ritonavir with a fixed COC resulted in a reduction of
the ethinylestradiol mean AUC by 41%, increased doses of COCs containing
ethinylestradiol, or alternate methods of contraception should be considered.
COCs may affect the metabolism of other drugs. Accordingly, plasma and tissue
concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
Tizanidine

COCs can enhance the hypotensive effect of tizanidine due to the inhibition of
tizanidine’s metabolism in CYP1A2. Caution should be used when prescribing to
COC users, because of the narrow therapeutic interval for tizanidine.
Levothyroxine
Estrogen therapy can result in decreased levels of free thyroxine and increase of TSH
among women with hypothyroidism in treatment with levothyroxine. The
combination can be used if dose adjustment is performed.
Note: The prescribing information of concomitant medications should be consulted to
identify potential interactions.
Laboratory tests
The use of contraceptive steroids may have an influence on the results of certain
laboratory analyses, including biochemical parameters of liver, thyroid, adrenal and
renal function, the plasma levels of (carrier) proteins, e.g. corticosteroid binding
globulin and lipid/lipoprotein fractions, parameters for carbohydrate metabolism and
parameters of coagulation and fibrinolysis. Changes generally remain within the
normal laboratory range.
4.6

Fertility, pregnancy and lactation

Pregnancy
Gedarel is not indicated in pregnancy.
If pregnancy occurs during treatment with Gedarel, further intake should be stopped.
However, most epidemiological studies have revealed neither an increased risk of
birth defects in children born to women who used COCs prior to pregnancy, nor a
teratogenic effect when COCs were taken inadvertently during early pregnancy.
The increased risk of VTE during the postpartum period should be considered when
re-starting Gedarel (see sections 4.2 and 4.4).
Breastfeeding
Lactation may be influenced by COCs as they may reduce the quantity and change the
composition of breast milk. Therefore, the use of COCs should generally not be
recommended until the nursing mother has completely weaned her child. Small
amounts of the contraceptive steroids and/or their metabolites may be excreted with
the milk, but there is no evidence that this adversely affects infant health.
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

As with all COCs, changes in vaginal bleeding patterns may occur, especially during
the first months of use. These may include changes in bleeding frequency (absent,
less, more frequent or continuous), intensity (reduced or increased) or duration.
During the first part of the treatment period, a large number (10-30%) of women can
expect side effects such as breast tenderness, feeling unwell and bleedings. These side
effects are usually temporary and disappear within 2-4 months.
Possibly related undesirable effects that have been reported in users of COC
containing 150 microgram desogestrel and 20 microgram ethinylestradiol (such as
Gedarel) or COC users in general are listed in the table below3. All ADRs are listed
by system organ class and frequency; very common (≥1/10), common (≥1/100 to
<1/10), uncommon (≥1/1,000 to <1/100) and rare (<1/1,000).
Organ Systems
Class

Very common
>1/10

Common
Uncommon
>1/100 to <1/10 >1/1,000 to
<1/100

Vaginal
candidiasis
Hypersensitivity

Infections and
infestations
Immune system
disorders
Metabolism and
nutrition
disorders
Psychiatric
disorders

Fluid retention

Nervous system
disorders

Depressed
mood,
Mood altered

Libido
decreased

Headache,
Dizziness,
Nervousness

Migraine

Libido
increased

Contact lens
intolerance

Eye disorders
Otosclerosis

Ear and
labyrinth
disorders
Vascular
disorders

Hypertension

Nausea,
Vomiting,
Abdominal pain Diarrhoea
Acne
Rash,
Urticaria

Gastrointestinal
disorders
Skin and
subcutaneous
tissue disorders

Reproductive

Rare
<1/1,000

Irregular

Amenorrhea,

Breast

Venous or
arterial
thromboembolism

Erythema
nodosum,
Erythema
multiforme,
Pruritus,
Alopecia
Vaginal

system and
breast disorders

bleeding

Breast pain,
Breast
tenderness,
Breast
hypertrophy,
Dysmenorrhea,
Premenstrual
syndrome

enlargement

discharge,
Breast discharge

Weight
Weight
General
increased
decreased
disorders and
administration
site conditions
3
The most appropriate MedDRA term to describe a certain adverse reaction is listed.
Synonyms or related conditions are not listed, but should be taken into account as
well.
Description of selected adverse reactions
An increased risk of arterial and venous thrombotic and thrombo-embolic events,
including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis
and pulmonary embolism has been observed in women using CHCs, which are
discussed in more detail in section 4.4;
Also a number of other undesirable effects have been reported in women using COCs,
which are discussed in more detail in section 4.4;
− Hypertension;
− Hormone-dependent tumours (e.g. liver tumours, breast cancer);
− Chloasma.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9

Overdose
There have been no reports of serious, harmful effects after overdose. Symptoms that
may occur in this case are: nausea, vomiting and, in young girls, slight vaginal
bleeding. There are not antidotes, and further treatment should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations; ATC
code: G03AA09
Mechanism of action
The contraceptive action of COCs is based on interaction of different factors, out of
which the most important is the inhibition of ovulation and changes in the cervical
secretion. Besides protection against pregnancy, COCs have several positive
properties which, next to the negative properties (see Warnings, Undesirable effects),
can be useful in deciding on the method of birth control. The cycle is more regular
and the menstruation is often less painful and bleeding is lighter. The latter may result
in a decrease in the occurrence of iron deficiency. In the largest multicenter trial
(n=23 258 cycles), the uncorrected Pearl Index is estimated at 0.1 (95% confidence
interval 0.0-0.3). Furthermore, 4.5% of the women reported absence of withdrawal
bleeding and 9.2% reported occurrence of irregular bleeding after 6 treatment cycles.
Gedarel is a COC with ethinylestradiol and the progestogen desogestrel.
Ethinylestradiol is a well known synthetic estrogen.
Desogestrel is a synthetic progestogen. After oral administration it has a strong
ovulation-inhibiting activity.
With the use of the higher-dosed COCs (50 µg ethinylestradiol) the risk of
endometrial and ovarian cancer is reduced. Whether this also applies to lower-dosed
COCs remains to be confirmed.
Paediatric population
No clinical data on efficacy and safety are available in adolescents below 18 years.
5.2

Pharmacokinetic properties

Desogestrel
Absorption
After oral administration of Gedarel, desogestrel is rapidly absorbed and converted
into 3-keto-desogestrel. Peak plasma levels are reached after 1.5 hours. The absolute
bioavailability of 3-keto-desogestrel is 62-81%.
Distribution
3-keto-desogestrel is 95.5-99% bound to the plasma proteins, mainly albumin and
SHBG. The ethinyl-oestradiol-induced increase in SHBG influences both the amount
of bindings and distribution of 3-keto-deosgestrel in the plasma proteins. As a
consequence the concentration of 3-keto-desogestrel rises slowly during treatment
until steady state is reached within 3-13 days.
Biotransformation
The phase-I metabolism of desogestrel includes cytochrome P-450 catalysed
hydroxylation and subsequent dehydrogenation at C3. The active metabolite of 3keto-desogestrel is further reduced, the degradation products are conjugated to
sulphate and glucuronides. Animal studies indicate that the enterohepatic circulation
has no relevance for the gestagenic activity of desogestrel.

Elimination
3-keto-desogestrel is eliminated with a mean half-life of approx. 31 hours (24-38
hours), plasma clearance varies from 5.0-9.5 l/hour. Desogestrel and its metabolites
are eliminated via the urine and in the faeces, either as free steroids or conjugates.
Ratio for elimination in urine or faeces is 1.5:1.
Steady-State Conditions
In steady-state conditions the serum level of 3-keto-desogestrel is elevated by two- to
three-fold.
Ethinylestradiol
Absporption
Ethinyl oestradiol is rapidly absorbed and peak plasma levels are reached after 1.5
hours. As a consequence of presystemic conjugation and first-pass metabolism the
absolute bioavailability is 60%. The area under the curve and Cmax may be expected
to rise slightly over time.
Distribution
Ethinyl oestradiol is 98.8% bound to the plasma proteins, almost exclusively to
albumin.
Biotransformation
Ethinyl oestradiol undergoes presystemic conjugation both in the mucosa of the small
intestine and in the liver. Hydrolysis of the direct conjugates of ethinyl oestradiol with
the aid of the intestinal flora gives ethinyl oestradiol, which can be re-absorbed, and
an enterohepatic circulation is hereby set up. The primary pathway of ethinyl
oestradiol metabolism is cytochrom P-450-mediated hydroxylation in which the
primary metabolites are 2-OH-EE and 2-methoxy-EE. 2-OH-EE is further
metabolised to chemically reactive metabolites.
Elimination
Ethinyl oestradiol disappears from plasma with a half-life of approx. 29 hours (26-33
hours), plasma clearance varies from 10-30 l/hour. The conjugates of ethinyl
oestradiol and its metabolites are excreted via urine and faeces (ratio 1:1).
Steady-state conditions
Steady-state conditions are obtained after 3 to 4 days, when the serum drug level is
approx. 30 to 40% higher than after the administration of a single dose.
5.3

Preclinical safety data
Toxicological studies have not revealed other effects than those, which can be
explained, based on the hormone profile of Gedarel.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Potato starch;
stearic acid;
all-rac-alpha-tocopherol;
lactose monohydrate;
magnesium stearate;
silica colloidal anhydrous;
povidone K 30;
quinoline yellow (E 104);
Tablet coating:
Hypromellose;
Macrogol 6000;
Propylene glycol.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Store below 30ºC. Store in the original package.

6.5

Nature and contents of container
PVC/PVDC-Aluminium blisters of 21 tablets per calendar blister strip available in
packs containing 1x21, 3x21, 6x21 or 13x21 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling
No special requirements.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Gedeon Richter Plc.
1103 Budapest, Gyömrői út 19-21.
Hungary

8

MARKETING AUTHORISATION NUMBER(S)
PL 04854/0060

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
05/07/2013

10

DATE OF REVISION OF THE TEXT
17/09/2014

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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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