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ESLARILA ED 0.02 MG/ 3 MG FILM-COATED TABLETS

Active substance(s): DROSPIRENONE / ETHINYLESTRADIOL

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1

NAME OF THE MEDICINAL PRODUCT

Eslarila ED 0.02 mg /3 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
21 white or almost white (active) film-coated tablets:
Each film-coated tablet contains 0.02 mg ethinylestradiol and 3 mg drospirenone.
Excipients with known effect:
Each film-coated tablet contains 48.53 mg of lactose monohydrate and 0.070 mg of soya
lecithin.
7 green placebo (inactive) film-coated tablets:
The tablet does not contain active substances.
Excipients: lactose anhydrous 37.26 mg and 0 sunset yellow (E110) 0.003 mg, indigo carmine
(E132), and quinoline yellow (E104).
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Film-coated tablet.
The active tablet is white or almost white, round, biconvex film-coated tablet, diameter about
6 mm. Engraving on one side: “G73”, the other side is without engraving.
The placebo tablet is green, round, biconvex film-coated tablet, diameter about 6 mm, without
engraving.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

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

4.2

Posology and method of administration

Posology
Route of administration: oral use

How to take Eslarila ED
The tablets must be taken every day at about the same time, if necessary with a little liquid, in the
order shown on the blister pack. Tablet taking is continuous. One tablet is to be taken daily for 28
consecutive days. Each subsequent pack is started the day after the last tablet of the previous pack.
Withdrawal bleeding usually starts on day 2-3 after starting the placebo tablets (last row) and may not
have finished before the next pack is started.

How to start Eslarila ED

No preceding hormonal contraceptive use (in the past month)
Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual
bleeding).


Changing from a combined hormonal contraceptive (combined oral contraceptive(COC),
vaginal ring, or transdermal patch)
The woman should start with Eslarila ED on the day after the last active tablet (the last tablet
containing the active substances) of her previous COC, but at the latest on the following the usual
tablet-free or placebo tablet interval of her previous COC.In case a vaginal ring or transdermal patch
has been used, the woman should start using Eslarila ED preferably on the day of removal, but at the
latest when the next application would have been due.


Changing from a progestogen-only-method (progestogen-only pill, injection, implant) or from a
progestogen-releasing intrauterine system (IUS))
The woman may switch any day from the progestogen-only pill (from an implant or the IUS on the
day of its removal, from an injectable when the next injection would be due) but should in all of these
cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

Following first-trimester abortion
The woman may start immediately. When doing so, she need not take additional contraceptive
measures.


Following delivery or second-trimester abortion
Women should be advised to start the use of Eslarila ED at day 21 to 28 after delivery or secondtrimester abortion. When starting later, the woman should be advised to additionally use a barrier
method for the first 7 days. However, if intercourse has already occurred, pregnancy should be
excluded before the actual start of COC use or the woman has to wait for her first menstrual period.
For breastfeeding women see section 4.6.

Management of missed tablets
Missed pills from the last row of the blister are placebo tablets and thus can be disregarded.. However,
they should be discarded to avoid unintentionally prolonging the placebo tablet phase. The following
advice only refers to missed active tablets (rows 1-3 of the blister):
If the user is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The
woman should take the tablet as soon as she remembers and should take further tablets at the usual
time.
If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The
management of missed tablets can be guided by the following two basic rules:
1.
2.

tablet-taking must never be discontinued for longer than 7 days
7 days of uninterrupted tablet-taking are required to attain adequate suppression of the
hypothalamic-pituitary-ovarian-axis.

Accordingly the following advice can be given in daily practice:


Week 1
The user should take the last missed tablet as soon as she remembers, even if this means taking
two tablets at the same time. She then continues to take tablets at her usual time. In addition, a
barrier method such as a condom should be used for the next 7 days. If intercourse took place in
the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are
missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy.



Week 2
The user should take the last missed tablet as soon as she remembers, even if this means taking
two tablets at the same time. She then continues to take tablets at her usual time. Provided that
the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is
no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet,
the woman should be advised to use extra precautions for 7 days.



Week 3
The risk of reduced reliability is imminent because of the forthcoming 7-day placebo tablet
phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can
still be prevented. By adhering to either of the following two options, there is therefore no need
to use extra contraceptive precautions, provided that in the 7 days preceding the first missed
tablet the woman has taken all the tablets correctly. If this is not the case, the woman should
follow the first of these two options and use extra precautions for the next 7 days as well.
1. The user should take the last missed tablet as soon as she remembers, even if this means
taking two tablets at the same time. She then continues to take tablets at her usual time until the

active tablets are used up. The 7 tablets from the last row (placebo tablets) must be discarded.
The next blister pack must be started right away. The user is unlikely to have a withdrawal bleed
until the end of the active tablets section of the second pack, but she may experience spotting or
breakthrough bleeding on tablet-taking days.
2. The woman may also be advised to discontinue active tablet-taking from the current blister
pack. She then should take tablets from the last row (placebo tablets) for up to 7 days, including
the days she missed tablets and subsequently continue with the next blister pack.
If the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet phase, the
possibility of a pregnancy should be considered.

Advice in case of gastro-intestinal disturbances
In case of severe gastro-intestinal disturbances (e.g. vomiting or diarrhoea), absorption may not be
complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after active tablet-taking, a new (replacement) tablet should be
taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablettaking if possible. If more than 12 hours elapse, the advice concerning missed tablets as given in
section 4.2 “Management of missed tablets” is applicable. If the woman does not want to change her
normal tablet-taking schedule, she has to take the extra tablet(s) from another blister pack.
How to postpone a withdrawal bleed
To delay a period the woman should continue with another blister pack of Eslarila ED without taking
the placebo tablets from her current pack. The extension can be carried on for as long as wished until
the end of the active tablets in the second pack. During the extension, the woman may experience
breakthrough bleeding or spotting. Regular intake of Eslarila ED is then resumed after the placebo
tablet phase.
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 placebo tablet phase 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).

4.3

Contraindications

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions
listed below. Should any of the conditions appear for the first time during COC use, the product
should be stopped immediately.
Combined hormonal contraceptives (CHCs) should not be used in the following conditions:




Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Hypersensitivity to peanut or soya.
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]).








4.4

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)
o A high risk of venous thromboembolism due to the presence of multiple risk factors
(see section 4.4)
Presence or rsik 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 antiphospholipid-antibodies (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
Presence or history of severe hepatic disease as long as liver function values have not returned
to normal.
Severe renal insufficiency or acute renal failure.
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).
Undiagnosed vaginal bleeding.

Special warnings and precautions for use

Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of Eslarila ED
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 doctorto determine whether the use of Eslarila ED 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 Eslarila ED 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 Eslarila ED, 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 drospirenone, 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

Extremely rarely, thrombosis has been reported to occur in CHC users 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).

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.

Eslarila ED 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, 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

Comment

Obesity (body mass index over 30
kg/m²)

Risk increases substantially as BMI rises.

Prolonged immobilisation, major
surgery, any surgery to the legs or
pelvis, neurosurgery, or major trauma

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.

Particularly important to consider if other risk factors
also present.

Antithrombotic treatment should be considered if
Eslarila ED has not been discontinued in advance.

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).

If a hereditary predisposition is suspected, the woman
should be referred to a specialist for advice before
deciding about any CHC use

Other medical conditions associated
with VTE

Cancer, systemic lupus erythematosus, haemolytic
uraemic syndrome, chronic inflammatory bowel disease
(Crohn’s disease or ulcerative colitis) and sickle cell
disease

Increasing age

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). Eslarila ED 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

Comment

Increasing age

Particularly above 35 years

Smoking

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.

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

Risk increases substantially as BMI increases.
Particularly important in women with additional risk

factors
Positive family history (arterial
thromboembolism ever in a sibling or
parent especially at relatively early age
e.g. below 50).

If a hereditary predisposition is suspected, the woman
should be referred to a specialist for advice before
deciding about any CHC use

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 associated
with adverse vascular events

Diabetes mellitus, hyperhomocysteinaemia, valvular
heart disease and atrial fibrillation, 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.
The presence of one serious risk factor or multiple risk factors for venous or arterial disease,
respectively, can also constitute a contra-indication. The possibility of anticoagulant therapy should
also be taken into account. COC users should be specifically pointed out to contact their physician in
case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use
should be discontinued. Adequate alternative contraception should be initiated because of the
teratogenicity of anticoagulant therapy (coumarins).


Tumours

An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in some
epidemiological studies, but there continues to be controversy about the extent to which this finding is
attributable to the confounding effects of sexual behaviour and other factors such as human papilloma
virus (HPV).

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 life-threatening 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.
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.


Other conditions

The progestin component in this product is an aldosterone antagonist with potassium-sparing
properties. In most cases, no increase of potassium levels is to be expected. In a clinical study,
however, in some patients with mild or moderate renal impairment and concomitant use of potassiumsparing medicinal products serum potassium levels slightly, but not significantly, increased during
drospirenone intake. Therefore, it is recommended to check serum potassium during the first treatment
cycle in patients presenting with renal insufficiency and a pretreatment serum potassium in the upper
reference range, and particularly during concomitant use of potassium-sparing medicinal products. See
also section 4.5.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of
pancreatitis when using COCs.
Although small increases in blood pressure have been reported in many women taking COCs,
clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC
use is justified. If, during the use of a COC in pre-existing hypertension, constantly elevated blood
pressure values or a significant increase in blood pressure do not respond adequately to
antihypertensive treatment, the COC must be withdrawn. 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 pruritus related
to cholestasis; gallstones; porphyria; systemic lupus erythematosus; haemolytic uremic syndrome;
Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of
angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until
markers of liver function return to normal. Recurrence of cholestatic jaundice and/or cholestasisrelated pruritus which previously occurred during pregnancy or during 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 low-dose COCs (containing <
0.05 mg ethinylestradiol). However, diabetic women should be carefully observed, particularly in the
early stage of COC use.
Worsening of endogenous depression, of epilepsy, of Crohn's disease and of ulcerative colitis has been
reported during 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.
The active film-coated tablets contain 48.53 mg of lactose monohydrate and the inactive ones contain
37.26 mg of lactose anhydrous per film-coated tablets. Patients with rare hereditary problems of
galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
The placebo film-coated tablets contain “sunset yellow” colouring agent which may cause allergic
reaction.
This medicinal product contains 0.070 mg soya lecitin per tablet. Patients with hypersensitivity to
peanut or soya should not take this medicine.

Medical examination/consultation
Prior to the initiation or reinstitution of Eslarila ED 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 {Invented name} 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 active tablets (see section 4.2),
gastro-intestinal disturbances during active tablet taking (see section 4.2) or concomitant medication
(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 non-hormonal 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 placebo tablet phase. 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

Note: The prescribing information of concomitant medications should be consulted to identify
potential interactions.

Influence of other medicinal products on drospirenone/ethinylestradiol
Interactions between oral contraceptives and other medicinal products may lead to breakthrough
bleeding and/or contraceptive failure. The following interactions have been reported in the literature.
Hepatic metabolism
Interactions can occur with drugs that induce hepatic enzymes which can result in increased clearance
of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, bosentan and
HIV-medication (e.g. ritonavir, nevirapine) and possibly also oxcarbazepine, topiramate, felbamate,
griseofulvin and products containing the herbal remedy St. John's Wort (Hypericum perforatum).
Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4
weeks after the cessation of drug therapy.
Interference with enterohepatic circulation
Contraceptive failures have also been reported with antibiotics, such as penicillins and tetracyclines.
The mechanism of this effect has not been elucidated.
Management
Women on short-term treatment with any of the above-mentioned classes of medicinal products or
individual active substances (hepatic enzyme-inducing medicine) besides rifampicin should
temporarily use a barrier method in addition to the COC, i.e. during the time of concomitant medicinal
product administration and for 7 days after their discontinuation.

For women on rifampicin a barrier method should be used in addition to the COC during the time of
rifampicin administration and for 28 days after its discontinuation.
In women on long term treatment with hepatic enzyme-inducing active substances, another reliable,
non-hormonal, method of contraception is recommended.
Woman on treatment with antibiotics (besides rifampicin, see above) should use the barrier method
until 7 days after discontinuation.
If concomitant medicinal product administration runs beyond the end of the active tablets in the COC
blister pack, the placebo tablets must be discarded and the next COC pack should be started right
away.
The main metabolites of drospirenone in human plasma are generated without involvement of the
cytochrome P450 system. Inhibitors of this enzyme system are therefore unlikely to influence the
metabolism of drospirenone.
• Influence of drospirenone/ethinylestradiol on other medicinal products
Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma
and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).
Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using
omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone at doses of
3 mg with the metabolism of other active substances is unlikely.

Other interactions
In patients without renal insufficiency, the concomitant use of drospirenone and ACE-inhibitors or
NSAIDs did not show a significant effect on serum potassium. Nevertheless, concomitant use of
drospirenone/ethinylestradiol with aldosterone antagonists or potassium-sparing diuretics has not been
studied. In this case, serum potassium should be tested during the first treatment cycle. See also
section 4.4.

Laboratory tests
The use of contraceptive steroids may influence the results of certain laboratory tests, including
biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier)
proteins, e.g. corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of
carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain
within the normal laboratory range. Drospirenone causes an increase in plasma renin activity and
plasma aldosterone induced by its mild antimineralocorticoid activity.

4.6

Fertility, pregnancy and lactation

Pregnancy
Drospirenone/ethinylestradiol is not indicated during pregnancy.

If pregnancy occurs during use of drospirenone/ethinylestradiol, the preparation should be withdrawn
immediately. Extensive 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 pregnancy.
Animal studies have shown undesirable effects during pregnancy and lactation (see section 5.3). Based
on these animal data, undesirable effects due to hormonal action of the active compounds cannot be
excluded. However, general experience with COCs during pregnancy did not provide evidence for an
actual undesirable effect in humans.
The available data regarding the use of drospirenone/ethinylestradiol during pregnancy are too limited
to permit conclusions concerning negative effects of drospirenone/ethinylestradiol on pregnancy,
health of the foetus or neonate. To date, no relevant epidemiological data are available.
The increased risk of VTE during the postpartum period should be considered when re-starting
Eslarila ED (see section 4.2 and 4.4).
Breast-feeding
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 breast-feeding
mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their
metabolites may be excreted with the milk during COC use. These amounts may affect the child.

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No effects on
ability to drive and use machines have been observed in users of COCs.

4.8

Undesirable effects

For serious undesirable effects in COC users see section 4.4.
The following adverse drug reactions have been reported during combined use of
drospirenone/ethinylestradiol:

Table 1: Drospirenone/ethinylestradiol 3 mg/ 0.02 mg, 21+7-day regimen - adverse reactions by
MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical
trial data.

System Organ Class
MedDRA

Frequency of adverse reactions
Common

Uncommon

Rare

version14.1

≥1/100 to <1/10

≥1/1,000 to <1/100

Infections and
infestations

Candidiasis
Herpes simplex

Immune system
disorders

Allergic reaction

Metabolism and
nutrition disorders

Increased appetite

Psychiatric disorders Emotional lability

Depression
Nervousness
Sleep disorder

Nervous system
disorders

Headache

≥1/10,000 to <1/1,000

Asthma

Paresthesia
Vertigo
Hypacusis

Ear and Labyrinth
disorders
Eye disorders

Visual disturbance

Cardiac disorders

Extrasystoles
Tachycardia

Vascular disorders

Hypertension
Hypotension
Migraine
Varicose veins

Respiratory, thoracic
and mediastinal
disorders

Pharyngitis

Gastrointestinal
disorders

Abdominal pain

Nausea
Vomiting
Gastroenteritis
Diarrhoea
Constipation
Gastrointestinal disorder

Skin and
subcutaneous tissue
disorders

Acne

Angioedema
Alopecia
Pruritus
Rash
Dry skin
Seborrhea
Skin disorder

Musculoskeletal and
connective tissue
disorders

Neck pain
Pain in extremity
Muscle cramps

Renal and urinary
disorders

Cystitis

Venous
thromboembolism
Arterial
thromboembolism

Erythema nodosum
Erythema multiforme

Reproductive system Breast pain
and breast disorders Breast enlargement
Breast tenderness
Dysmenorrhea
Metrorrhagia

Breast neoplasm
Fibrocystic breast
Galactorrhea
Ovarian cyst
Hot flushes
Menstrual disorder
Amenorrhea
Menorrhagia
Vaginal candidiasis
Vaginitis
Genital discharge
Vulvovaginal disorder
Vaginal dryness
Pelvic pain
Papanicolaou smear
suspicious
Libido decreased

General disorders
and administration
site conditions

Edema
Asthenia
Pain
Excessive thirst
Sweating increased

Investigations

Weight increase

Weight decrease

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.
The following serious adverse events have been reported in women using COCs, which are discussed
in section 4.4 Special warning and precautions for use:








Hypertension;
Liver tumours;
Occurrence or deterioration of conditions for which association with COC use is not conclusive:
Crohn's disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus
erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic
jaundice;
Chloasma;
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use
until markers of liver function return to normal.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate
symptoms of angioedema.

The frequency of diagnosis of breast cancer is very slightly increased among OC users. As breast
cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk
of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and
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 Yellow Card Scheme at
www.mhra.gov.uk/yellowcard.

4.9.

Overdose
There has not yet been any experience of overdose with drospirenone/ethinylestradiol. On the
basis of general experience with combined oral contraceptives, symptoms that may possibly
occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are
no antidotes and further treatment should be symptomatic.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations
ATC code: G03AA12
Pearl Index for method failure: 0.11 (upper two-sided 95 % confidence limit: 0.60).
Overall Pearl Index (method failure + patient failure): 0.31 (upper two-sided 95 % confidence
limit: 0.91)
Mechanism of action
The contraceptive effect of Eslarila ED is based on the interaction of various factors, the most
important of which are seen as the inhibition of ovulation and the changes in the endometrium.
Eslarila ED is a combined oral contraceptive with ethinylestradiol and the progestogen
drospirenone. In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild
antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid
activity. This gives drospirenone a pharmacological profile closely resembling the natural
hormone progesterone.
There are indications from clinical studies that the mild antimineralocorticoid properties result
in a mild antimineralocorticoid effect.

5.2

Pharmacokinetic properties



Drospirenone

Absorption
Orally administered drospirenone is rapidly and almost completely absorbed. Maximum
concentrations of the active substance in serum of about 38 ng/ml are reached at about 1-2 h after
single ingestion. Bioavailability is between 76 and 85%. Concomitant ingestion of food has no
influence on the bioavailability of drospirenone.
Distribution
After oral administration, serum drospirenone levels decrease with a terminal half-life of 31 h.
Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG)
or corticoid binding globulin (CBG). Only 3-5% of the total serum concentrations of the active
substance are present as free steroid. The ethinylestradiol-induced increase in SHBG does not
influence the serum protein binding of drospirenone. The mean apparent volume of distribution of
drospirenone is 3.7 ± 1.2 l/kg.
Biotransformation
Drospirenone is extensively metabolized after oral administration. The major metabolites in the
plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system.
Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 and has demonstrated a
capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome
P450 2C19 in vitro.
Elimination
The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 ml/min/kg. Drospirenone is
excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with
the feces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with
the urine and feces is about 40 h.
Steady-state conditions
During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about
70 ng/ml are reached after about 8 days of treatment. Serum drospirenone levels accumulated by a
factor of about 3 as a consequence of the ratio of terminal half-life and dosing interval.
Special Populations
Effect of renal impairment
Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance
CLcr, 50-80 ml/min) were comparable to those of women with normal renal function. The serum
drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr,
30-50 ml/min) compared to those in women with normal renal function. Drospirenone treatment was
also well tolerated by women with mild and moderate renal impairment. Drospirenone treatment did
not show any clinically significant effect on serum potassium concentration.

Effect of hepatic impairment
In a single dose study, oral clearance (CL/F) was decreased approximately 50% in volunteers with
moderate hepatic impairment as compared to those with normal liver function. The observed decline in
drospirenone clearance in volunteers with moderate hepatic impairment did not translate into any
apparent difference in terms of serum potassium concentrations. Even in the presence of diabetes and
concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalemia)
an increase in serum potassium concentrations above the upper limit of the normal range was not
observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate
hepatic impairment (Child-Pugh B).
Ethnic groups
No clinically relevant differences in the pharmacokinetics of drospirenone or ethinylestradiol between
Japanese and Caucasian women have been observed.


Ethinylestradiol

Absorption
Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of
about 33 pg/ml are reached within 1-2 hours after single oral administration. Absolute bioavailability
as a result of pre-systemic conjugation and first-pass metabolism is approximately 60%. Concomitant
intake of food reduced the bioavailability of ethinylestradiol in about 25% of the investigated subjects
while no change was observed in the others.
Distribution
Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterized
by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to
serum albumin (approximately 98.5 %), and induces an increase in the serum concentrations of SHBG
and corticoid binding globulin (CBG). An apparent volume of distribution of about 5 l/kg was
determined.
Biotransformation
Ethinylestradiol is subject to pre-systemic conjugation in both small bowel mucosa and the liver.
Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of
hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as
conjugates with glucuronides and sulphate. The metabolic clearance rate of ethinylestradiol is about
5 ml/min/kg.
Elimination
Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of
ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is
about 1 day.
Steady-state conditions
Steady-state conditions are reached during the second half of a treatment cycle and serum levels of
ethinylestradiol accumulate by a factor of about 2.0 to 2.3.

5.3

Preclinical safety data
In laboratory animals, the effects of drospirenone and ethinylestradiol were confined to those
associated with the recognised pharmacological action. In particular, reproduction toxicity
studies revealed embryotoxic and fetotoxic effects in animals which are considered as species
specific. At exposures exceeding dose in users of drospirenone and ethinylestradiol, effects on
sexual differentiation were observed in rat fetuses but not in monkeys.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core (active):
Lactose monohydrate
Maize starch
Maize starch, pregelatinised
Macrogol poly(vinyl alcohol) grafted copolymer
Magnesium stearate
Film-coating (active):
Poly(vinyl alcohol)
Titanium dioxide (E171)
Talc
Macrogol 3350
Lecithin (soya)

Tablet core (placebo):
Cellulose, microcrystalline
Lactose anhydrous
Maize starch, pregelatinised
Magnesium stearate
Silica, colloidal anhydrous
Film-coating (placebo):

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol 3350
Talc
Indigo carmine (E132)
Quinoline yellow (E104)
Iron oxide black (E172)
Sunset yellow FCF (E110)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
Do not store above 25°C. Store in the original package in order to protect from light.

6.5.

Nature and contents of container
Eslarila ED film-coated tablets are packaged in PVC/PE/PVDC-Al blister packs. The blisters
are packed into folding box with patient leaflet and etui storage bag is enclosed in each box.
Pack sizes:
1×28 film-coated tablets

3×28 film-coated tablets
6×28 film-coated tablets
13×28 film-coated tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
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)
PL04854/0100

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/06/2011

10

DATE OF REVISION OF THE TEXT
18/07/2014

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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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