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YACELLA 0.03 MG/3 MG TABLETS

Active substance(s): DROSPIRENONE / ETHINYLESTRADIOL / DROSPIRENONE / ETHINYLESTRADIOL / DROSPIRENONE / ETHINYLESTRADIOL

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Yacella 0.03 mg/3 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 0.03 mg ethinylestradiol and 3 mg drospirenone.
Excipients with known effect:
Each tablet contains 72 mg of lactose, 0.032 mg of E110, susnset yellow FCF
and 0.12 mg of E102, tartrazine.
For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Tablet

Round, yellow, uncoated biconvex tablet with ‘143’ debossed on one side and
other side plain.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Oral contraception.

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

4.2

Posology and method of administration
Route of administration: oral use
How to take Yacella Tablets
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. One tablet is to be taken
daily for 21 consecutive days. Each subsequent pack is started after a 7-day
tablet-free interval, during which time a withdrawal bleed usually occurs. This
usually starts on day 2-3 after the last tablet and may not have finished before
the next pack is started.
How to start Yacella Tablets
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 Yacella Tablets preferably 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 day 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 Yacella
Tablets 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 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
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. tablet-taking must never be discontinued for longer than 7 days
2. 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 regular tablet-free interval, 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
tablet-free interval. 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 tablets correctly. If this is not the case, she 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. The next blister pack must be started as soon as
the current blister pack is finished, i.e., no gap should be left between
packs. The user is unlikely to have a withdrawal bleed until the end 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 tablet-taking from the
current blister pack. She should then have a tablet-free interval of 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
first normal tablet-free interval, 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 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 tablet-taking 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
Yacella Tablets 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 Yacella Tablets 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).
Additional information on special populations
Children and adolescents
Yacella is only indicated after menarche. Based on epidemiological data
collected on more than 2000 adolescent women aged below 18 years, there are
no data indicating that safety and efficacy in this young age group is different
from that known in women aged above 18 years.

4.3

Contraindications
Combined hormonal contraceptives (CHCs) should not be used in the following
conditions. Should any of the conditions appear for the first time during CHC 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-IIIdeficiency, 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 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 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
Hypersensitivity to the active substances or to any of the excipients of Yacella
tablets listed in section 6.1

4.4

Special warnings and precautions for use
Warnings



If any of the conditions or risk factors mentioned below is present, the suitability of
Yacella Tablets 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
Yacella tablets should be discontinued.
• In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. In case
anticoagulant therapy is started, adequate alternative contraception should be initiated
because of the teratogenicity of anticoagulant therapy (coumarins).
• Circulatory Disorders
Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) carries an increased 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 Yacella Tablets 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 Yacella Tablets, 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 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).
Yacella Tablets are 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 Risk increases substantially as BMI
kg/m²)
rises.
Particularly important to consider if
other risk factors also present.
Prolonged immobilisation, major In these situations it is advisable to
surgery, any surgery to the legs or discontinue use of the patch/pill/ring
pelvis, neurosurgery, or major trauma (in the case of elective surgery at
least four weeks in advance) and not
resume until two weeks after
complete remobilisation. Another
Note:
temporary
immobilisation method of contraception should be
including air travel >4 hours can also be a used
to
avoid
unintentional
risk factor for VTE, particularly in pregnancy.
women with other risk factors
Antithrombotic treatment should be
considered if Yacella has not been
discontinued in advance.
Positive family history (venous If a hereditary predisposition is
thromboembolism ever in a sibling or suspected, the woman should be

parent especially at a relatively early
age e.g. before 50).
Other medical conditions associated
with VTE

Increasing age

referred to a specialist for advice
before deciding about any CHC use
Cancer,
systemic
lupus
erythematosus, haemolytic uremic
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). Yacella tablets are
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

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.

Hypertension
Obesity (body mass index over 30 Risk increases substantially as BMI
kg/m2)
increases.
Particularly important in women with
additional risk factors
Positive family history (arterial If a hereditary predisposition is
thromboembolism ever in a sibling or suspected, the woman should be
parent especially at relatively early referred to a specialist for advice
age e.g. below 50).
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 Diabetes mellitus,
with adverse vascular events
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.

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 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.
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 progestogen component in Yacella Tablets 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 potassium-sparing 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 pre-treatment serum
potassium in the upper reference range, and particularly during concomitant use of
potassium sparing medicinal products. See also section 4.5.
Women with hypertriglyceridaemia, 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 preexisting 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 oestrogens 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 cholestasis-related 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.
This medicinal product contains 72 mg lactose per tablet. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption who are on a lactose-free diet should take this amount into
consideration

Medical examination/consultation
Prior to the initiation or reinstitution of Yacella Tablets 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). 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 oral 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 (see section
4.2), gastrointestinal disturbances (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 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
Note: The prescribing information of concomitant medications should be
consulted to identify potential interactions.


Influence of other medicinal products on Yacella Tablets
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 enzymeinducing 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.
Women 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 tablets in the COC blister pack, the next COC pack should be started
without the usual tablet-free interval.
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 Yacella Tablets 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 Yacella
Tablets 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
Yacella Tablets is not indicated during pregnancy.
If pregnancy occurs during use of Yacella Tablets, 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 Yacella Tablets during pregnancy are
too limited to permit conclusions concerning negative effects of Yacella
Tablets 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 Yacella Tablets (see section 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 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 use of Yacella
Tablets:

Body System

Frequency of adverse reactions
Common
≥ 1/100 to <1/10

Uncommon
≥ 1/1,000 to <
1/100

Immune system

Rare
≥ 1/10,000 to
< 1/1000
hypersensitivity
asthma

Psychiatric disorders
Nervous system
Ear and labyrinth
Vascular system

depressive mood
headache
migraine

Gastrointestinal system nausea
Skin and
subcutaneous system

Reproductive system
and breast

menstrual disorders,
intermenstrual
bleeding,
breast pain,
breast tenderness,
leukorrhoea,
vaginal moniliasis

General

hypertension,
hypotension
vomiting,
diarrhoea
acne,
eczema,
pruritus,
alopecia
breast enlargement,
changes in libido,
vaginitis

hypacusis
VTE or ATE

erythema nodosum
erythema multiforme

breast section

fluid retention,
body weight
changes
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:
-

-

Venous thromboembolic disorders;
Arterial thromboembolic disorders;
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.
Interactions
Breakthrough bleeding and/or contraceptive failure may result from interactions of
other drugs (enzyme inducers) with oral contraceptives (see section 4.5).

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, Website: www.mhra.gov.uk/yellowcard .

4.9

Overdose
There has not yet been any experience of overdose with Yacella Tablets. 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 (ATC): Progestogens and estrogens, fixed
combinations
ATC Code: G03AA 12
Pearl Index for method failure: 0.09 (upper two-sided 95 % confidence limit:
0.32).
Overall Pearl Index (method failure + patient failure): 0.57 (upper two-sided
95 % confidence limit: 0.90).
The contraceptive effect of Yacella Tablets 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.
Yacella Tablets 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 of Yacella Tablets 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.
Metabolism
Drospirenone is extensively metabolized after oral administration. The major
metabolites in the plasma are the acid form of drospirenone, generated by
opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-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 faeces and urine at an
excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with
the urine and faeces is about 40 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 hyperkalaemia) 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
Ethinylestradiol is rapidly and completely absorbed after ingestion. After
administration of 30 µg, peak plasma concentrations of 100 pg/ml are reached
1-2 hours after ingestion. Ethinylestradiol undergoes an extensive first-pass
effect, which displays great inter-individual variation. The absolute
bioavailability is approx. 45 %.
Distribution
Ethinylestradiol has an apparent volume of distribution of 5 l/kg and binding
to plasma proteins is approx. 98 %. Ethinylestradiol induces the hepatic
synthesis of SHBG and CBG. During treatment with 30 µg ethinylestradiol the
plasma concentration of SHBG increases from 70 to about 350 nmol/l.
Ethinylestradiol passes in small amounts into breast milk (0.02 % of the dose).
Metabolism
Ethinylestradiol is metabolised completely (metabolic plasma clearance 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. The elimination halflife is 20 hours.
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 1.4 to 2.1.

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 those in users of Yacella Tablets, effects on sexual differentiation
were observed in rat foetuses but not in monkeys.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate,
Maize starch,
Povidone K25,
Magnesium stearate,
Crospovidone (Type B),
Tartrazine Aluminium Lake ( E102),
Sunset Yellow FCF Aluminium Lake (E 110),
Indigo Carmine Aluminium Lake (E 132).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions

6.5

Nature and contents of container
PVC/PVDC/Aluminium blister pack. Each blister is packed in a
Polyester/Aluminium/Natural Polyethylene Pouch.
Pack sizes: 21 tablets 3x21 tablets 6x21 tablets 13x21 tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Morningside Healthcare Limited
115 Narborough Road
Leicester LE3 0PA
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20117/0134

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
09/03/2015

10

DATE OF REVISION OF THE TEXT
21/12/2016

Expand Transcript

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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