SUMMARY OF PRODUCT CHARACTERISTICS

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Seasonique 150 micrograms/30 micrograms and 10 micrograms Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pink film-coated tablet contains 150 micrograms of levonorgestrel and 30 micrograms of ethinylestradiol.

Each white film-coated tablet contains 10 micrograms of ethinylestradiol. Excipients with known effect:

pink tablets: lactose 63.02 mg per tablet, allura red (E129) 0.169 mg per tablet and brilliant blue FCF (E133) 0.009 mg per tablet white tablets: lactose 69.20 mg per tablet For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Pink, round, biconvex tablets, around 5.7 mm in diameter, embossed “172” on one side and “T” on the other side.

White, round, biconvex tablets, around 5.7 mm in diameter, embossed “173” on one side and “T” on the other side.

White tablets are provided in the fifth (last) row on the third blister. Only the third blister contains five rows of tablets and is of rectangular shape.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Oral contraception.

The decision to prescribe Seasonique should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE),

and how the risk of VTE with Seasonique compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).

4.2 Posology and method of administration

Posology

Seasonique is an extended-regimen oral contraceptive where tablets are taken continuously for 91 days. Each subsequent 91-day pack is started the day after the last tablet of the previous pack.

Seasonique pack consists of 84 combination tablets of 150 micrograms levonorgestrel and 30 micrograms ethinylestradiol, and 7 tablets of 10 micrograms ethinylestradiol.

How to use Seasonique

Tablet-taking is continuous for 91 days. One tablet is to be taken by mouth at the same time every day in the order shown on the blister pack.

One pink tablet containing levonorgestrel and ethinylestradiol is taken daily for 84 consecutive days, followed by one white ethinylestradiol tablet for 7 days, during which time withdrawal bleeding usually occurs.

How to start Seasonique

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 91 consecutive days. One pink tablet should be taken daily for 84 consecutive days, followed by one white tablet for 7 consecutive days. A scheduled withdrawal bleeding should occur during the 7 days that the white tablets are taken.

Each subsequent 91-day cycle is started without interruption on the same day of the week on which the patient began her first dose of Seasonique, following the same schedule.

•    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). The women may start Seasonique later (i.e. days 2-5 of the cycle), but should in this case be advised to additionally use a barrier method for the first 7 days of tablet-taking.

•    Changing from a combined hormonal contraceptive (combined oral contraceptive

(COC), vaginal ring, or transdermal patch)

The woman should start with Seasonique on the day after the last active tablet (the last tablet containing the active substances) of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Seasonique 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 needs 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.

The increased risk of VTE during the postpartum period should however be considered (see section 4.4 and 4.6).

For breastfeeding women see section 4.6.

Management of missed tablets

Contraceptive reliability may be reduced if taking the pink tablets is forgotten and particularly if one forgets to take the first tablets from the blister pack.

If it is found within 12 hours of the usual time of taking that one pink tablet has been forgotten, the tablet that was forgotten should be taken immediately, and the treatment should be continued normally by taking the next tablet at the usual time.

If it is found more than 12 hours after the normal time of taking that one or several pink tablets have been forgotten, 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:

Missed_pink levonorgestrel/ethinylestradiol tablets

•    During Day 1 - Day 7 (week 1)

The woman should take the last missed pink 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 sexual 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 white tablet phase, the higher the risk of a pregnancy.

•    During Day 8 - Day 77 (week 2 to week 11)

The woman should take the last missed pink 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.

•    During Day 78 - Day 84 (week 12)

The risk of reduced reliability is imminent because of the forthcoming 7 day ethinylestradiol-only tablet interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. There is 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 use extra precautions for the next 7 days and she should stop taking the pink combined tablets and take the white ethinylestradiol-only tablet minus the tablets she has missed, in order to induce withdrawal bleeding. Subsequently, she can start a new cycle of Seasonique.

Missed white ethinylestradiol tablets (week 13)

The missed tablets should be omitted and further tablets continued at the usual time until the pack is finished. No additional contraception precautions are required.

If the woman has no withdrawal bleeding during the week 13 (while taking the white ethinylestradiol tablets), the possibility of pregnancy must be ruled out before a new 91-day cycle is started.

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, the women should apply the advice given for missed tablets.

If the woman does not want to change her normal tablet-taking schedule, she can take the extra pink tablet(s) from the last row (week 12).

Paediatric population

The efficacy and safety of Seasonique in women of reproductive age under 18 years have not been established.

Method of administration: oral use

4.3 Contraindications

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

•    Presence or risk of venous thromboembolism (VTE)

•    Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])

•    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

•    Major surgery with prolonged immobilisation (see section 4.4)

•    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)

•    Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)

•    Cerebrovascular disease - current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)

•    Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).

•    History of migraine with focal neurological symptoms.

•    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)

•    Undiagnosed vaginal bleeding

•    In association with herbal remedy St. John's Wort (hypericum perforatum)

•    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 Seasonique should be discussed with the woman.

In the event of aggravation, exacerbation 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 Seasonique 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. It is not yet known how the risk with Seasonique compares with other levonorgestrel-containing CHCs. The decision to use Seasonique should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, 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).

Epidemiological studies in women who use low dose combined oral contraceptives (<50 pg ethinylestradiol) have found that out of 10,000 women between about 6 and 12 will develop a VTE in one year.

It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 6¹ will develop a VTE in one year.

The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.

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

It is not known how Seasonique influences the occurrence of such events in comparison to other levonorgestrel containing CHCs.

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).

Seasonique 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 on 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).

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

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.
Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors	Antithrombotic treatment should be considered if Seasonique has not been discontinued in advance.
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). Seasonique 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.

Tumours

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

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

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

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

Other conditions

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs.

Although small increases in blood pressure have been reported in many women taking CHCs, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of CHC use is justified. If, during the use of a CHC in preexisting hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the CHC must be withdrawn. Where considered appropriate, CHC 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 CHC use, but the evidence of an association with CHC 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 CHC 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 CHCs.

Although CHCs 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 CHCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed, particularly in the early stage of CHC use.

Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during CHC 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 CHCs.

Medical examination/consultation

Prior to the initiation or reinstitution of Seasonique 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 Seasonique 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 (see section 4.2) or concomitant medication (see section 4.5).

Reduced cycle control

With all CHCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first 3 months of use. The evaluation of any irregular bleeding should be conducted if the bleeding persists.

In the Seasonique clinical trials scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 3 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles.

If unscheduled spotting or bleeding occurs, the woman should be instructed to continue on the same regimen. If the bleeding is persistent or prolonged, the woman should be advised to consult her physician.

Seasonique tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Seasonique pink tablets contain the azo colouring agents Allura red AC Aluminium Lake (E129) and Brilliant Blue FCF Aluminium Lake (E133) that can cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

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

Influence of other medicinal products on Seasonique

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, vemurafenib 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.

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.

Influence of Seasonique on other medicinal products

The concomitant use of COCs and lamotrigine has been shown to reduce lamotrigine levels by about 50%. This interaction may be due to the estrogen component since it does not occur with progestagens given alone. In a patient already treated with lamotrigine, a close clinical monitoring and a possible dosage adjustment at the beginning and the stop of the contraceptive may be necessary. Conversely, starting oral contraception during lamotrigine titration should be avoided.

Laboratory tests

The use of COCs may change the results of some 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. The changes generally remain within the normal laboratory range.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs.

4.6 Fertility, pregnancy and lactation

Pregnancy

Seasonique is not indicated during pregnancy.

If pregnancy occurs during use of Seasonique, the treatment 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 increased risk of VTE during the postpartum period should be considered when re-starting Seasonique (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.

Fertility

Seasonique is indicated for the prevention of pregnancy.

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

The pivotal clinical trial that evaluated the safety and efficacy of Seasonique was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18-40, of whom 1,006 took at least one dose of Seasonique.

The most commonly reported treatment-emergent adverse reactions were irregular and/or heavy uterine bleeding, weight gain and acne.

Additional adverse reactions identified during post-marketing experience with Seasonique are reported as frequency unknown.

The frequencies are defined as follows: Very common (^ 1/10); Common (^ 1/100 to <1/10); Uncommon ( £ 1/1,000 to <1/100); Rare (£ 1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data)

System organ class	Very common	Common	Uncommon	Rare	Not known
Infections and infestations			Fungal infection, vaginosis fungal, vaginitis bacterial, bladder infection, gastroenteritis, sinusitis, pahryngitis, vaginal candidiasis, vaginal infection, vaginitis
Neoplasms benign, malignant and unspecified (inc cysts and polyps)			Fibrocystic breast disorder, uterine fibroids, uterine fibroids aggravated
Blood and lymphatic system disorders			Anaemia
Immune system disorders					Hypersensiti y reaction
Metabolism and nutrition disorders			Appetite increased, anorexia, appetite decreased, diabetes mellitus, insulin

System organ class	Very common	Common	Uncommon	Rare	Not known
			resistance
Psychiatric disorders		Mood changes, libido decreased, depression	Irritability, anxiety, depression aggravated, depressed mood, emotional distress, insomnia, affect lability, anxiety aggravated, orgasm abnormal, paranoia
Nervous system disorders		Headache1, migraine2	Dizziness, hyperaesthesia, hypoaesthesia		Loss of consciousne:
Ear and labyrinth disorders			Vertigo
Cardiac disorders			Palpitations, tachycardia
Vascular disorders			Hot flushes, hypertension, hypertension aggravated, orthostatic hypotension	Arterial thromboe mbolism (ATE) Venous thromboe mbolism (VTE)
Respiratory, thoracic and mediastinal disorders			Sinus congestion	Pulmona ry embolis m, pulmonar y thrombos is
Gastrointestinal disorders		Nausea3, abdominal pain	Vomiting, dyspepsia, diarrhoea, constipation, nausea aggravated
Hepatobiliary disorders			Cholecystitis, cholelithiasis
Skin and subcutaneous tissue disorders		Acne5	Rash, hair growth abnormal, hair texture abnormal, hypotrichosis, nail disorder, night sweats, photosensitivity reaction, skin hyperpigmentation		Alopecia
Musculoskeletal and connective tissue disorders			Peripheral swelling, back pain, muscle spasm, arthralgia, joint stiffness, myalgia, neck pain		Pain in extremity
Reproductive	Metrorrha	Menorrhagi	Vulvovaginal dryness,

System organ class	Very common	Common	Uncommon	Rare	Not known
system and breast disorders	gia	a, breast tenderness, dysmenorrh oea	uterine spasm, breast pain, menstruation irregular, breast engorgement, breast enlargement, dyspareunia, postcoital bleeding, vaginal discharge, breast discharge, genital pruritus, genital rash, pelvic pain, polycystic ovaries, vulvar disorder, vulvovaginal discomfort
General disorders and administration site conditions			Fatigue, oedema6, pain, chest pain, feeling hot, influenza like illness, malaise, pyrexia
Investigations		Weight increased	Blood pressure increased, lipids increased, weight decreased

¹    including headache aggravated and tension headache

²    including migraine aggravated and migraine with aura

³    including nausea aggravated

⁴    including abdominal distension, abdominal pain upper and abdominal pain lower

⁵    including acne aggravated

⁶    including peripheral oedema

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 CHCs, which are discussed in section 4.4 Special warning and precautions for use:

•    Venous thromboembolic    disorders

•    Arterial thromboembolic    disorders

•    Hypertension

•    Liver tumours

•    Depression

•    Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, migraine, 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

There have been no reports of serious adverse effects from overdose of oral contraceptives. 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 treatment should be symptomatic.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, Hormonal contraceptives for systemic use, Progestogens and estrogens, fixed combinations ATC Code: G03AA07

Overall Pearl Index (18-35 years of age): 0.76 (upper two-sided 95% confidence limit 1.76)

Pearl Index for method failure (18-35 years of age): 0.26 (upper two-sided 95% confidence limit 0.80)

Overall Pearl Index (18-40 years of age): 0.67 (upper two-sided 95% confidence limit 1.56)

The contraceptive effect of COCs 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.

Seasonique is a 91 day extended-regimen oral contraceptive that reduces scheduled, withdrawal bleeding to four episodes per year. In addition, in the final 7 days of the extended-regimen (on Days 85-91) Seasonique includes 10 micrograms of ethinylestradiol instead of placebo to enhance ovarian follicular suppression and decrease the risk of escape ovulation however is not known to which extent contraceptive efficacy is modified.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Seasonique in all subsets of the paediatric population in contraception (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Ethinylestradiol and levonorgestrel are absorbed with maximum plasma concentrations occurring within 2 hours after oral administration. Levonorgestrel is completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinylestradiol is absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, its bioavailability is approximately 43%.

Steady-state

During the continuous use of Seasonique serum levonorgestrel levels increase about 3-fold and ethinylestradiol levels about 1.6-fold at Day 21 compared to Day 1 of the treatment.

The daily exposure to levonorgestrel and ethinylestradiol on Day 21, corresponding to the end of a typical 3-week contraceptive regimen, and on Day 84, at the end of an extended-regimen, were similar without any further accumulation of drug.

Distribution

Levonorgestrel is highly protein-bound, principally to sex hormone binding globulin (SHBG) and serum albumin. Ethinylestradiol is highly (about 95%), but nonspecifically bound to serum albumin. Ethinylestradiol does not bind to SHBG, but induces an increase in the serum concentrations of SHBG, influencing the relative distribution of levonorgestrel into different protein fractions (increase in SHBG-bound fraction and decrease in albumin-bound fraction).

Biotransformation

Following absorption, levonorgestrel is conjugated at the 17P-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma.

First-pass metabolism of ethinylestradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinylestradiol by hepatic cytochrome P-450 3A4. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Elimination

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in faeces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Seasonique was about 34 hours.

Ethinylestradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinylestradiol after a single dose of Seasonique was found to be about 18 hours.

5.3    Preclinical safety data

In laboratory animals, the effects of levonorgestrel and ethinylestradiol were confined to those associated with the recognised pharmacological action. In particular, reproduction toxicity studies revealed embryotoxic and fetotoxic effects in animals.

Non-clinical data for ethinylestradiol and levonorgestrel reveal no special hazard for humans based on repeat-dose toxicity studies, genotoxicity and carcinogenic potential do not indicate any relevant risks for humans. However, it should be born in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

6    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

Pink film-coated tablets:

Tablet core:

Anhydrous lactose Hypromellose Microcrystalline Cellulose Magnesium Stearate Tablet coating:

Hypromellose Titanium Dioxide (E171)

Macrogol 400

Allura Red AC Aluminium Lake (E129)

Polysorbate 80

Brilliant Blue FCF Aluminium Lake (E133)

White film-coated tablets:

Tablet core:

Anhydrous lactose Polacrilin Potassium Microcrystalline Cellulose Magnesium Stearate Tablet coating:

Titanium Dioxide (E171)

Polydextrose FCC Hypromellose Triacetin Macrogol 8000

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

Store in the original package in order to protect from light and moisture

6.5    Nature and contents of container

Each pack contains 91 film-coated tablets (84 pink tablets and 7 white tablets) in three blisters:

2 X 28 pink film-coated tablets + 1 X (28 pink film-coated tablets + 7 white film-coated tablets)

Three PVC/TE / PVDC // Al blisters are placed inside a carton folder, placed into foil pouch and box.

6.6    Special precautions for disposal

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

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road,

Hampden Park,

Eastbourne,

East Sussex BN22 9AG UNITED KINGDOM

MARKETING AUTHORISATION NUMBER(S)

PL 00289/1900

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/10/2015

10    DATE OF REVISION OF THE TEXT

08/10/2016