SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Gedarel 20/150 microgram film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 micrograms ethinylestradiol and 150 micrograms desogestrel

Excipient with known effect: 64.3 mg lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

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

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Oral contraception

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

4.2 Posology and method of administration

Posology

How to take Gedarel

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

Each subsequent pack is started after a 7-day tablet-free interval; during this tablet-free interval a menstruation- like withdrawal bleeding occurs. This bleeding usually begins on the 2nd or 3rd day after ingestion of the last tablet and it may not have ceased, before the next pack is started.

How to start Gedarel

No preceding intake of COCs (within the last month)

The tablet intake should be started on day 1 of the normal menstrual cycle (i.e. on the first day on which the woman has a menstrual bleeding). Tablet intake is also allowed to start on day 2-5, but during the first cycle concurrent use of a barrier method for the first 7 days of tablet intake is advisable.

Changing from another combined hormonal contraceptive (combined oral contraceptive (COC), combined contraceptive vaginal ring or transdermalpatch)

The woman should start taking Gedarel preferably on the day after the last active tablet (the last tablet containing the active substance) of her previous COC, but at the latest on the day following the usual tablet-free interval or following the last placebo tablet of her previous COC.

In case a vaginal ring or a transdermal patch has been used, the woman should start using Gedarel preferably on the day of removal, but at the latest when the next application would have been due.

If the woman has been using her previous method consistently and correctly and if it is reasonably certain that she is not pregnant she may also switch from her previous COC on any day of the cycle.

Changing from progestogen only products (progetogen-only-pills, injection, implant) or from a progestogen-releasing intrauterine system (IUS)

The woman can change from progestogen-only pills on any day (changing from implant or IUS on the day of its removal; changing from injection when the next injection should have been given) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

After abortion in the 1st trimester

Tablet intake should start immediately. In this case no further contraceptive measures are necessary.

After delivery or abortion in the 2nd trimester For breast-feeding women - see section 4.6.

The woman should be advised to start the pill on day 21-28 after delivery or abortion in the 2nd trimester. She should be advised to use a barrier method concurrently during the first 7 days of tablet intake if she starts the pill later. In case she has already had intercourse, pregnancy should be excluded before she starts tablet intake, or she should wait for her first menstrual bleeding.

Forgotten tablets

If the tablet intake is forgotten for less than 12 hours, contraceptive protection is not reduced. The woman should take the forgotten tablet as soon as she remembers, and the remaining tablets are taken as usual.

If the tablet intake is forgotten for more than 12 hours, contraceptive protection may be reduced. The following two basic rules should be considered in case of forgotten tablets:

1.    Continuous tablet intake must not be interrupted for longer than a period of 7 days.

2.    7 days of uninterrupted tablet intake are required to achieve sufficient suppression of the hypothalamus-pituitary-ovarian-axis.

Thus, the following advice may be given for daily practice:

Week 1

The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day. She should concurrently use a barrier method, e.g. a condom, for the next 7 days. If intercourse has taken place during the preceding 7 days, the possibility of pregnancy should be considered. The more tablets are forgotten and the closer they are to the regular tablet-free period, the higher the risk of pregnancy is.

Week 2

The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day. Provided that the tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet, it is not necessary to take further contraceptive measures. However, if this is not the case, or if more than 1 tablet has been forgotten, the woman should be advised to use another contraceptive method for 7 days.

Week 3

The risk of reduced contraceptive protection is imminent due to the next tablet-free period. However, this risk may be prevented by adjusting tablet intake. Thus, it is not necessary to take further contraceptive measures if one of the two alternatives below is followed, provided that all tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet. If this is not the case, the woman should be advised to follow the first of the two alternatives and concurrently use another contraceptive method for the next 7 days.

1. The user should take the last forgotten tablet as soon as she remembers even if it means that she has to take 2 tablets at the same time. Then she continues taking the tablets at the usual time of the day. She will begin taking the next pack immediately after taking the last tablet in the present pack, i.e. there is no break between the packs. It is not very likely that the user will have her menstrual bleeding until the end of the second pack, but she may experience spotting or break-through bleeding on the days she is taking tablets.

2. The woman may also be advised to stop taking tablets from the present pack.

In that case she should keep a tablet-free period of up to 7 days, including those days when she forgot tablets, and then continue with the next pack.

In case the woman has forgotten tablets and then does not have her menstrual bleeding in the first normal tablet-free period, the possibility of pregnancy should be considered

Precautions in case of vomiting or severe diarrhoea

If vomiting or severe diarrhoea occur within 3-4 hours after tablet intake, the tablet may not be absorbed completely. Therefore, the precautions concerning forgotten tablets as described in section “Forgotten tablets” 4.2. apply. If the woman does not want to change her usual tablet intake, she has to take the necessary extra tablet(s) from another pack.

How to postpone a withdrawal bleed

Postponing the monthly withdrawal bleed is not an indication of this product. To delay a period the woman should continue with another blister pack of Gedarel without a tablet-free interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of Gedarel is then resumed after the usual 7-day tablet-free interval

To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming tablet-free interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

Paediatric population

The safety and efficacy of desogestrel in adolescents below 18 years has not yet been established. No data are available.

Method of administration For oral administration.

4.3 Contraindications

Combined hormonal contraceptives (CHCs) should not be used in the following conditions.

Should any of the condition appear for the first time during COCs use, the product should be stopped immediately.

- Presence or risk of venous thromboembolism (VTE)

o Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]). o Known hereditary or acquired predisposition for venous

thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency. o Major surgery with prolonged immobilisation (see section 4.4).

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.

-    Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.

-    Presence or history of severe hepatic disease as long as liver function values

have not returned to normal.

-    Presence or history of liver tumours (benign or malignant).

-    Known or suspected sex steroid-influenced malignancies (e.g. of the genital

organs or the breasts)

-    Endometrial hyperplasia.

-    Undiagnosed vaginal bleeding.

-    Known or suspected pregnancy.

-    Hypersensitivity to the active substances or to any of the excipients listed in

section 6.1.

4.4 Special warnings and precautions for use

Warnings

If any of the conditions or risk factors mentioned below is present, the suitability of Gedarel should be discussed with the woman.

In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Gedarel should be discontinued.

Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Gedarel may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Gedarel, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).

It is estimated¹ that out of 10,000 women who use a CHC containing desogestrel between 9 and 12 women will develop a VTE in one year; this compares with about 6² in women who use a levonorgestrel-containing CHC.

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

VTE may be fatal in 1-2% of cases.

Number of VTE events per 10,000 women in one year

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.

Risk factors for VTE

The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

Gedarel is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor,

it is possible that the increase in risk is greater than the sum of the individual factors in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for VTE

Risk factor	Comment
Obesity (body mass index over 30 kg/m2).	Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present.
Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma.	In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Gedarel has not been discontinued in advance.
Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors.
Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50).	If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
Other medical conditions associated with VTE.	Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.
Increasing age.	Particularly above 35 years.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6 week period of the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:

-    unilateral swelling of the leg and/or foot or along a vein in the leg;

-    pain or tenderness in the leg which may be felt only when standing or walking;

-    increased warmth in the affected leg; red or discoloured skin on the leg. Symptoms of pulmonary embolism (PE) can include:

-    sudden onset of unexplained shortness of breath or rapid breathing;

-    sudden coughing which may be associated with haemoptysis;

-    sharp chest pain;

-    severe light headedness or dizziness;

-    rapid or irregular heartbeat.

Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).

Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Gedarel is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for ATE

Risk factor	Comment
Increasing age.	Particularly above 35 years.
Smoking.	Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.
Hypertension.
Obesity (body mass index over 30 kg/m2).	Risk increases substantially as BMI increases. Particularly important in women with additional risk. factors.
Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).	If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
Migraine.	An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.
Other medical conditions associated with adverse vascular events.	Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.

Symptoms of ATE

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of a cerebrovascular accident can include:

-    sudden numbness or weakness of the face, arm or leg, especially on one side of the body;

-    sudden trouble walking, dizziness, loss of balance or coordination;

-    sudden confusion, trouble speaking or understanding;

-    sudden trouble seeing in one or both eyes;

-    sudden, severe or prolonged headache with no known cause;

-    loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA). Symptoms of myocardial infarction (MI) can include:

-    pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;

-    discomfort radiating to the back, jaw, throat, arm, stomach;

-    feeling of being full, having indigestion or choking;

-    sweating, nausea, vomiting or dizziness;

-    extreme weakness, anxiety, or shortness of breath;

-    rapid or irregular heartbeats.

Occurrence of one or more of these symptoms may be a reason for immediate discontinuation of Gedarel usage.

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with CHC use.

Tumours

Epidemiological studies indicate that the long-term use of COCs displays a risk factor for the development of cervical cancer in women infected with human papillomavirus (HPV). However, there is still uncertainty about the extent to which this finding may be influenced by confounding effects (e.g. differences in number of sexual partners or in use of barrier contraceptives).

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.

Other conditions

Women with hypertriglyceridaemia or a family history thereof, may be at an increased risk of pancreatitis when taking COCs.

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. Relationship between COC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: Jaundice and/or itching in connection with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss; (hereditary) angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrent of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using COCs. However, diabetic women should be carefully observed while taking COCs.

Crohn’s disease and ulcerative colitis and worsening of endogenous depression and epilepsy have been associated with COC use.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.

Gedarel contains <65 mg lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

When counselling the choice of contraceptive method(s), all the above information should be taken into account.

Medical examination/consultation

Prior to the initiation or reinstitution of Gedarel a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contra-indications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Gedarel compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy

The efficacy of COCs may be reduced in the event of e.g., missed tablets (section 4.2), gastro-intestinal disturbances (section 4.2) or concomitant medication (section 4.5).

Herbal preparations containing St. John's wort (Hypericum perforatum) should not be used while taking Gedarel due to the risk of decreased plasma concentrations and reduced clinical effects of Gedarel (see section 4.5).

Reduced cycle control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.

If bleeding irregularities persist or occur after previously regular cycles, then nonhormonal causes should be considered and adequate, diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.

In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions

Interactions between COCs and other drugs may lead to breakthrough bleeding and/or COC failure. The following interactions have been reported in the literature:

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

Contraceptive failures have also been reported with antibiotics, such as ampicillin and tetracyclines. The mechanism of this effect has not been elucidated.

Women on treatment with any of these drugs should temporarily use a barrier method in addition to the COC, or choose another method of contraception.

With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. In case of long-term treatment with microsomal enzyme inducing drugs another method of contraception should be considered.

Women on treatment with antibiotics (except rifampicin and griseofulvin, which also act as microsomal enzyme-inducing drugs) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the tablets in the COC pack, the next COC pack should be started without the usual tablet free interval.

Women on short term treatment (up to one week) with some of the above mentioned groups of drugs or individual drugs should temporarily use a barrier method concomitantly with the COCs, i.e. in the period of other concomitant drug intake and for 7 days after cessation of this drug. Women taking microsomal enzyme-inducing drugs (e.g. rifampicin) should use a barrier method concomitantly with intake of COCs for the period in which she is treated with rifampicin and for 28 days after cessation of rifampicin. In case other concomitant drug intake exceeds the number of tablets in the COCs pack, she should start the next pack of pills without keeping the usual tablet-free period.

It is recommended by experts to increase the contraceptive steroid dosage for women who are on long-term treatment with liver enzyme inducing drugs. If a high contraceptive dosage is not advisable or this high dosage turns out to be insufficient or unsafe, e.g. in case of irregular bleeding, another contraceptive method should be advised.

The herbal preparation St.John’s wort (Hypericum perforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect. Break-through bleeding and unintended pregnancies have been reported. This is due to induction of drug metabolising enzymes by St.John’s wort.

The inducing effect may persist for at least 2 weeks after cessation of treatment with St.John’s wort.

Concomitant administration of ritonavir with a fixed COC resulted in a reduction of the ethinylestradiol mean AUC by 41%, increased doses of COCs containing ethinylestradiol, or alternate methods of contraception should be considered.

COCs may affect the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Tizanidine

COCs can enhance the hypotensive effect of tizanidine due to the inhibition of tizanidine’s metabolism in CYP1A2. Caution should be used when prescribing to COC users, because of the narrow therapeutic interval for tizanidine.

Levothyroxine

Estrogen therapy can result in decreased levels of free thyroxine and increase of TSH among women with hypothyroidism in treatment with levothyroxine. The combination can be used if dose adjustment is performed.

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

Laboratory tests

The use of contraceptive steroids may have an influence on the results of certain laboratory analyses, including biochemical parameters of liver, thyroid, adrenal and renal function, the plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters for carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.6 Fertility, pregnancy and lactation

Pregnancy

Gedarel is not indicated in pregnancy.

If pregnancy occurs during treatment with Gedarel, further intake should be stopped. However, most epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy.

The increased risk of VTE during the postpartum period should be considered when re-starting Gedarel (see sections 4.2 and 4.4).

Breastfeeding

Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should generally not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk, but there is no evidence that this adversely affects infant health.

4.7 Effects on ability to drive and use machines

No effects on the ability to drive and use machines have been observed.

4.8 Undesirable effects

As with all COCs, changes in vaginal bleeding patterns may occur, especially during the first months of use. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration.

During the first part of the treatment period, a large number (10-30%) of women can expect side effects such as breast tenderness, feeling unwell and bleedings. These side effects are usually temporary and disappear within 2-4 months.

Possibly related undesirable effects that have been reported in users of COC containing 150 microgram desogestrel and 20 microgram ethinylestradiol (such as Gedarel) or COC users in general are listed in the table below³. All ADRs are listed by system organ class and frequency; very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100) and rare (<1/1,000).

Organ Systems Class	Very common >1/10	Common >1/100 to <1/10	Uncommon >1/1,000 to <1/100	Rare <1/1,000
Infections and infestations				Vaginal candidiasis
Immune system disorders				Hypersensitivity
Metabolism and nutrition disorders			Fluid retention
Psychiatric disorders		Depressed mood, Mood altered	Libido decreased	Libido increased
Nervous system disorders		Headache, Dizziness, Nervousness	Migraine
Eye disorders				Contact lens intolerance
Ear and labyrinth disorders			Otosclerosis
Vascular disorders			Hypertension	Venous or arterial thromboembolism
Gastrointestinal disorders		Nausea, Abdominal pain	Vomiting, Diarrhoea
Skin and subcutaneous tissue disorders		Acne	Rash, Urticaria	Erythema nodosum, Erythema multiforme, Pruritus, Alopecia
Reproductive	Irregular	Amenorrhea,	Breast	Vaginal

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4;

Also a number of other undesirable effects have been reported in women using COCs, which are discussed in more detail in section 4.4;

-    Hypertension;

-    Hormone-dependent tumours (e.g. liver tumours, breast cancer);

-    Chloasma.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations; ATC code: G03AA09

Mechanism of action

The contraceptive action of COCs is based on interaction of different factors, out of which the most important is the inhibition of ovulation and changes in the cervical secretion. Besides protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warnings, Undesirable effects), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. In the largest multicenter trial (n=23 258 cycles), the uncorrected Pearl Index is estimated at 0.1 (95% confidence interval 0.0-0.3). Furthermore, 4.5% of the women reported absence of withdrawal bleeding and 9.2% reported occurrence of irregular bleeding after 6 treatment cycles.

Gedarel is a COC with ethinylestradiol and the progestogen desogestrel. Ethinylestradiol is a well known synthetic estrogen.

Desogestrel is a synthetic progestogen. After oral administration it has a strong ovulation-inhibiting activity.

With the use of the higher-dosed COCs (50 pg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to lower-dosed COCs remains to be confirmed.

Paediatric population

No clinical data on efficacy and safety are available in adolescents below 18 years.

5.2 Pharmacokinetic properties

Desogestrel

Absorption

After oral administration of Gedarel, desogestrel is rapidly absorbed and converted into 3-keto-desogestrel. Peak plasma levels are reached after 1.5 hours. The absolute bioavailability of 3-keto-desogestrel is 62-81%.

Distribution

3-keto-desogestrel is 95.5-99% bound to the plasma proteins, mainly albumin and SHBG. The ethinyl-oestradiol-induced increase in SHBG influences both the amount of bindings and distribution of 3-keto-deosgestrel in the plasma proteins. As a consequence the concentration of 3-keto-desogestrel rises slowly during treatment until steady state is reached within 3-13 days.

Biotransformation

The phase-I metabolism of desogestrel includes cytochrome P-450 catalysed hydroxylation and subsequent dehydrogenation at C3. The active metabolite of 3-keto-desogestrel is further reduced, the degradation products are conjugated to sulphate and glucuronides. Animal studies indicate that the enterohepatic circulation has no relevance for the gestagenic activity of desogestrel.

Elimination

3-keto-desogestrel is eliminated with a mean half-life of approx. 31 hours (24-38 hours), plasma clearance varies from 5.0-9.5 l/hour. Desogestrel and its metabolites are eliminated via the urine and in the faeces, either as free steroids or conjugates. Ratio for elimination in urine or faeces is 1.5:1.

Steady-State Conditions

In steady-state conditions the serum level of 3-keto-desogestrel is elevated by two- to three-fold.

Ethinylestradiol

Absporption

Ethinyl oestradiol is rapidly absorbed and peak plasma levels are reached after 1.5 hours. As a consequence of presystemic conjugation and first-pass metabolism the absolute bioavailability is 60%. The area under the curve and Cmax may be expected to rise slightly over time.

Distribution

Ethinyl oestradiol is 98.8% bound to the plasma proteins, almost exclusively to albumin.

Biotransformation

Ethinyl oestradiol undergoes presystemic conjugation both in the mucosa of the small intestine and in the liver. Hydrolysis of the direct conjugates of ethinyl oestradiol with the aid of the intestinal flora gives ethinyl oestradiol, which can be re-absorbed, and an enterohepatic circulation is hereby set up. The primary pathway of ethinyl oestradiol metabolism is cytochrom P-450-mediated hydroxylation in which the primary metabolites are 2-OH-EE and 2-methoxy-EE. 2-OH-EE is further metabolised to chemically reactive metabolites.

Elimination

Ethinyl oestradiol disappears from plasma with a half-life of approx. 29 hours (26-33 hours), plasma clearance varies from 10-30 l/hour. The conjugates of ethinyl oestradiol and its metabolites are excreted via urine and faeces (ratio 1:1).

Steady-state conditions

Steady-state conditions are obtained after 3 to 4 days, when the serum drug level is approx. 30 to 40% higher than after the administration of a single dose.

5.3 Preclinical safety data

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

6.1    List of excipients

Tablet core:

Potato starch; stearic acid;

all-rac-alpha-tocopherol; lactose monohydrate; magnesium stearate; silica colloidal anhydrous; povidone K 30; quinoline yellow (E 104);

Tablet coating:

Hypromellose;

Macrogol 6000;

Propylene glycol.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions for    storage

Store below 30°C. Store in the original package.

6.5    Nature and contents of    container

PVC/PVDC-Aluminium blisters of 21 tablets per calendar blister strip available in packs containing 1x21, 3x21, 6x21 or 13x21 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for    disposal    and other handling

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Gedeon Richter Plc.

1103 Budapest, Gyomroi ut 19-21.

Hungary

8    MARKETING AUTHORISATION NUMBER(S)

PL 04854/0060

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/07/2013

10 DATE OF REVISION OF THE TEXT

17/09/2014

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

2

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.