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MINKIAN 0.02 MG/ 3 MG FILM-COATED TABLETS

Active substance(s): DROSPIRENONE / ETHINYLESTRADIOL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Minkian 0.02 mg/3 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

24 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.
4 green placebo (inactive) film-coated tablets:
The tablet does not contain active substances.
Excipients with known effect: lactose anhydrous 37.26 mg, sunset yellow (E110) 0.003 mg.
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 Minkian should take into consideration the individual
woman’s current risk factors, particularly those for venous thromboembolism (VTE),
and how the risk of VTE with Minkian compares with other combined hormonal
contraceptives (CHCs) (see sections 4.3 and 4.4).

4.2

Posology and method of administration

Route of administration: oral use
How to take Minkian
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 23 after starting the placebo tablets (last row) and may not have finished before the
next pack is started.
How to start Minkian

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 Minkian 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 Minkian 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 second-trimester
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
Placebo tablets from the last (4th) row of the blister 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:
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 4 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:


Day 1-7
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.



Day 8-14
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.



Day 15-24
The risk of reduced reliability is imminent because of the forthcoming 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 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 until the active tablets are used up. The 4 placebo tablets from
the last row 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 should then take placebo tablets from the last row for up
to 4 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 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 Minkian
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 Minkian 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 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

Special warnings and precautions for use

Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of
Minkian 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 Minkian 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 Minkian 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 Minkian, 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

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.

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).
Minkian 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 Risk increases substantially as BMI rises.
kg/m²)
Particularly important to consider if other risk
factors also present.
Prolonged immobilisation, major
In these situations it is advisable to discontinue
surgery, any surgery to the legs or use of the pill (in the case of elective surgery at
pelvis, neurosurgery, or major
least four weeks in advance) and not resume
trauma
until two weeks after complete remobilisation.
Another method of contraception should be used
to avoid unintentional pregnancy.
Antithrombotic treatment should be considered
if Minkian 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).
Other medical conditions
associated with VTE

Increasing age

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). Minkian 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

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

Other medical conditions
associated with adverse vascular
events

If a hereditary predisposition is suspected, the
woman should be referred to a specialist for
advice before deciding about any CHC use
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
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 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 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 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 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 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.
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 lecithin per tablet. Patients with
hypersensitivity to peanut or soya should not take this medicine.
Medical examination/consultation
Prior to the initiation or reinstitution of Minkian 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 Minkian 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 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 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 generallyseen 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.
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 active
tablets in the current 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 ACEinhibitors 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 combined 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 Minkian (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 and ethinylestradiol:
Table 1: Drospirenone/ethinylestradiol 3 mg/0.02 mg, 24+4 day regimen adverse drug reactions which have been associated with the use as oral
contraceptive or in the treatment of moderate acne vulgaris according to the
MedDRA system organ classes and MedDRA terms. The frequencies are based
on clinical trial data
System Organ
Class
(MedDRA

Frequency of adverse reactions
Common

Uncommon

Rare

Not known

version 14.1)

( 1/100 to
<1/10)

( 1/1,000 to
<1/100)

( 1/10,000 to
<1/1,000)

Infections and
infestations

Candidiasis

Blood and
lymphatic
system
disorders

Anaemia,
Thrombocythaemi
a

Immune system
disorders

Allergic reaction

Endocrine
disorders

Endocrine disorder

Metabolism and
nutrition
disorders

Increased appetite,
Anorexia,
Hyperkalaemia,
Hyponatraemia

Psychiatric
disorders

Emotional
lability

Depression,
Libido decreased,
Nervousness,
Somnolence

Anorgasmia,
Insomnia

Nervous system
disorders

Headache

Dizziness,
Paresthesia

Vertigo,
Tremor

Eye disorders

Conjunctivitis,
Dry eye,
Eye disorder

Cardiac
disorders

Tachycardia

Vascular
disorders

Migraine,
Varicose vein,
Hypertension

Venous
thromboembolism
Arterial
thromboembolism,
Phlebitis,
Vascular disorder,
Epistaxis,
Syncope

Gastrointestinal Nausea
disorders

Abdominal pain,
Vomiting,
Dyspepsia,
Flatulence,
Gastritis,

Abdomen
enlarged,
Gastrointestinal
disorder,
Gastrointestinal

(cannot be
estimated from
the available
data)

Hypersensitivity

Diarrhoea

fullness, Hiatus
hernia,
Oral candidiasis,
Constipation,
Dry mouth
Biliary pain,
Cholecystitis

Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders

Acne,
Pruritus,
Rash

Chloasma,
Erythema
Eczema,
multiforme
Alopecia,
Dermatitis
acneiform,
Dry skin,
Erythema
nodosum,
Hypertrichosis,
Skin disorder,
Skin striae,
Contact dermatitis,
Photosensitive
dermatitis,
Skin nodule

Musculoskeletal
and connective
tissue disorders

Back pain,
Pain in extremity,
Muscle cramps

Breast pain,
Reproductive
Metrorrhagia
system and
breast disorders *,
Amenorrhea

Vaginal
candidiasis, Pelvic
pain,
Breast
enlargement,
Fibrocystic breast,
Uterine / Vaginal
bleeding*,
Genital discharge,
Hot flushes,
Vaginitis,
Menstrual
disorder,
Dysmenorrhea,
Hypomenorrhea,
Menorrhagia,
Vaginal dryness,
Papanicolaou
smear suspicious

Dyspareunia,
Vulvovaginitis,
Postcoital bleeding
Withdrawal
bleeding,
Breast cyst,
Breast
hyperplasia,
Breast neoplasm,
Cervical polyp,
Endometrial
atrophy,
Ovarian cyst,
Uterine
enlargement

General
disorders and
administration

Asthenia,
Sweating
increased,

Malaise

site conditions

Edema
(Generalized
edema,
Peripheral edema,
Face edema)

Investigations

Weight increase

Weight decrease

* bleeding irregularities usually subside during continued treatment
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: 0.41 (upper two-sided 95% confidence limit:
0.85).
Overall Pearl Index (method failure + patient failure): 0.80 (upper two-sided
95 % confidence limit: 1.30)
Mechanism of action
The contraceptive effect of Minkian 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.
Minkian 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.
Two multicenter, double blind, randomized, placebo controlled studies were
performed to evaluate the efficacy and safety of drospirenone and
ethinylestradiol in women with moderate acne vulgaris.
After six months of treatment, in comparison with placebo, combined use of
drospirenone and ethinylestradiol showed a statistically significantly greater
reduction of 15.6% (49.3% versus 33.7%) in inflammatory lesions, 18.5%
(40.6% versus 22.1%) in non-inflammatory lesions, and 16.5% (44.6% versus
28.1%) in total lesion counts. In addition, a higher percentage of subjects,
11.8% (18.6% versus 6.8%), showed a ‘clear’ or ‘almost clear’ rating on the
Investigator’s Static Global Assessment (ISGA) scale.

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 4,5-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 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 (ChildPugh 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 nonspecifically 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 those 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
Minkian 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 size:
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)
PL04854/0098

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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