This information is intended for use by health professionals

1. Name of the medicinal product

Aidulan 30/75 microgram film-coated tablets

2. Qualitative and quantitative composition

Each tablet contains:

Ethinylestradiol 30 micrograms.

Gestodene 75 micrograms

Excipient with known effect: Lactose

Each tablet also contains 50 mg of lactose monohydrate

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film coated tablets.

White to off white round, biconvex, approximately 5mm diameter, film coated tablets debossed with “GE3” on one side and plain on the other side.

4. Clinical particulars
4.1 Therapeutic indications

Oral contraception

The decision to prescribe Aidulan 30/75 should take into consideration the individual woman's current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Aidulan 30/75 compares with other CHCs (see sections 4.3 and 4.4).

4.2 Posology and method of administration

How to use Aidulan 30/75

Tablets must be taken every day at about the same time, in accordance with the instructions written on the package. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after keeping a tablet-free interval. Withdrawal bleed occurs usually 2-3 days after the last tablet and should not finish before the next pack is started.

How to start Aidulan 30/75

No preceding hormonal contraceptive use in the last month

Taking of the tablets should begin the first day of the woman's natural cycle (i.e. the first day of the woman's menstrual bleeding). One may begin taking the Pills on 2nd to 5th day, but in these cases it is recommended that a barrier method also be used (e.g. condom or spermicide) for the first 7 days, while Pills are taken during the first cycle.

Changing from a combined contraceptive (combined oral contraceptive (COC), vaginal ring or transdermal patch) to Aidulan

The woman should start taking Aidulan the next day after having taken the last active tablet of her previous pack of contraceptive pills – but no later than the day after the usual tablet-free or placebo-tablet period of her previous contraceptive pill.

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

Changing from a progestin-only method (progestin-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS)

The woman may change from progestogen-only pills (POPs) any day. The first tablet should be taken the day after any tablet of the POP pack. When changing from an implant or the IUS, Aidulan should be started the day when the implant is removed. When changing from injections, Aidulan should be started when the next injection is to be given. In all these cases the woman is advised to use also a barrier method for the first 7 days of taking the Pills.

Following a first trimester abortion

Aidulan can be used immediately, while another additional contraceptive method is not needed.

Following delivery or a second-trimester abortion

Women should be advised to start at day 21 to 28 day 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 occured, 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.

Paediatric population

Paediatric data are not available. Safety and efficacy of COCs have been established in adult women of reproductive age.

Missed tablets

Missing a tablet for less than 12 hours does not diminish the contraceptive protection. The woman should take the tablet as soon as she remembers, and proceed taking the rest of the tablets as usual.

Missing a tablet for more than 12 hours can diminish the contraceptive protection. The two following rules may be helpful in dealing with missed tablets.

1. Taking tablets should never be delayed by a period longer than 7 days.

2. It takes 7 days of uninterrupted ingestion of the tablets to achieve sufficient suppression of the hypothalamus-pituitary-ovarian axis.

Thus, the following advice can be given in daily practice:

Week 1

The user should take the last missed tablet as soon as she remembers, even if this means that she needs to take 2 tablets at the same time. From then on she should continue to take the tablets at the usual time. At the same time she should use a barrier method, i.e. condom, for the next 7 days. If she had intercourse during the previous 7 days, she should consider the possibility that she might be pregnant. The more tablets have been missed, and the closer this happened to the monthly tablet-free period, the higher the risk of pregnancy is.

Week 2

The user should take the last missed tablet as soon as she remembers, even if it means that she has to take 2 tablets at the same time. From then on, she should go ahead with taking the tablets at the usual time. If the tablets have been taken correctly for the 7 days prior to the missed tablet, it is not necessary to take any additional contraceptive precautions. If this is not the case, however, or if more than 1 tablet has been missed, the woman should be advised to use another birth-control method for 7 days.

Week 3

The risk of reduced protection is imminent because of the approaching tablet-free period. The reduced contraceptive protection can be prevented, however, by adjusting the intake of the tablets. It is, therefore, not necessary to take any additional contraceptive precautions, provided that the tablets have been taken correctly for the 7 days prior to the missed tablet, if one follows any of the following choices. If this is not the case, the woman should be advised to go ahead according to the first of the two opportunities, and at the same time use another birth-control method for 7 days.

− The user should take the last missed tablet as soon as she remembers even if it means that she needs to take 2 tablets at the same time. From then on, she should continue to take the tablets at the usual time. She should start the next pack immediately after having taken the last tablet from the current pack; that means no pause between packs. The user will probably not get her menstruation before the end of the second pack, but she may experience spotting or withdrawal bleeding the days when she takes the tablets.

− The woman can also be advised to stop taking tablets from the current pack. In that case she should observe a tablet-free period for up to 7 days, including the days when she missed the tablets, and then continue with the next pack.

If the woman missed the tablets, and subsequently did not get her menstruation in the first normal tablet-free period, she should consider the possibility that she may be pregnant.

What to do in case of vomiting/diarrhoea

If vomiting occurs within 3-4 hours after having taken a tablet, absorption may not be complete. In this case the advice concerning the missed tablets, described above should be followed. Diarrhoea may reduce the efficacy by preventing full absorption. If the woman does not want to change her usual tablet intake, she should take the required extra tablet(s) from another blister pack.

In case of longer lasting or severe gastrointestinal symptoms, the woman should be advised to use another contraceptive method and/or to contact her physician.

How to advance or delay menstruation

In exceptional cases only, menstruation can be delayed as described below.

To delay menstruation, the woman should continue with another pack of Aidulan without observing the tablet-free period. Menstruation can be delayed as long as is desired up to the end of the second pack, but no longer. While menstruation is being delayed the woman may experience withdrawal bleeding or spotting. Regular intake of Aidulan should be resumed after the normal tablet-free period of 7 days.

To move menstruation to a weekday other than that on which the woman is used to having it under the current tablet schedule, she can be advised to shorten the next tablet-free period by as many days as she wishes. The shorter the pause, the higher the risk that she will not get her menstruation and will have withdrawal bleeding or spotting while she is taking the next pack (which is also true when menstruation is being delayed).

4.3 Contraindications

Combined hormonal contraceptives (CHCs) should not be used in the following conditions. Should any of the conditions appear for the first time during 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

− Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

− Acute and chronic disorders of hepatic functions (including Dubin-Johnson syndrome, Rotor syndrome), hepatic tumours indicated currently or in the past, indicated idiopathic jaundice or pruritus during pregnancy.

− Current or previous pancreatitis if associated with serious hypertriglyceridaemia.

− Hormone-dependent tumours (dependent on the level of sexual steroidal hormones, e.g. breast or endometrial carcinoma) at present or in the anamnesis, both confirmed and suspected.

− Bleeding from genitals of unexplained reasons.

− Pregnancy or suspected pregnancy.

− Aidulan 30/75 is contraindicated for concomitant use with the medicinal products containing ombittasvir/paritaprevir/ritonavir and dasabuvir, (see sections 4.4 and section 4.5).

4.4 Special warnings and precautions for use

Warnings:

If any of the conditions or risk factors mentioned below is present, the suitability of Aidulan 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 Aidulanshould 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 Aidulan 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 Aidulan, 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 estimated that out of 10,000 women who use a CHC containing gestodene, between 9 and 12 women will develop a VTE in one year. 1 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).

Aidulan 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).

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

Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors

In these situations it is advisable to discontinue use of the patch/pill/ring (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 Aidulan 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). Aidulan 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).

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 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

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.

Medical examination/consultation

Prior to the initiation or reinstitution of Aidulan 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 Aidulan 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 oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy

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

Reduced cycle control

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

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

In some women withdrawal bleeding may not occur during the 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.

These tablets contain 50 milligrams of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions between ethinylestradiol (EE) and other substances may lead to decreased or increased serum EE concentrations, respectively.

Decreased EE serum concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the COC.

During concomitant use of EE-containing products and substances that may lead to decreased EE serum concentrations, it is recommended that a non-hormonal back-up method of birth control (such as condoms and spermicide) be used in addition to the regular intake of Aidulan. In case of prolonged use of such substances COCs should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased EE serum concentrations, use of a non-hormonal back-up method is recommended for at least 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have lead to induction of hepatic microsomal enzymes, resulting in decreased EE serum concentrations. It may sometimes take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use and rate of elimination of the inducing substance.

Examples for substances that may decrease serum EE concentrations:

− Any substance that reduces gastrointestinal transit time

− Substances that induce hepatic microsomal enzymes, such as rifampicin, rifabutin, barbiturates, primidone, carbamazepine, phenylbutazone, phenytoin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil and possibly also oxcarbazepine, felbamate, ritonavir and nevirapine

− Hypericum perforatum, also known as St. John's wort (possibly by induction of hepatic microsomal enzymes)

− Certain antibiotics (e.g. penicillins, tetracyclines), by a decrease of enterohepatic circulation of estrogens.

Examples for substances that may increase serum EE concentrations:

− Atorvastatin

− Competitive inhibitors of sulphation in the gastrointestinal wall, such as ascorbic acid (vitamin C) and paracetamol

− Substances that inhibit cytochrome P 450 3A4 isoenzymes such as indinavir, fluconazole, voriconazole and troleandomycin.

Troleandomycin may increase the risk of intrahepatic cholestasis during co-administration with COCs.

EE may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation or by other mechanisms. Accordingly, plasma and tissue concentrations may either be increased (e.g. cyclosporine, theophylline, corticosteroids) or decreased (e.g. lamotrigine, levothyroxin, valproate).

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

Interactions with laboratory tests

− The use of oral contraception affects the result of some laboratory tests including biochemical parameters of liver function (including a decrease in bilirubin and alkaline phosphatase), thyroid function (increased total T3 and T4 due to increased TBG, decreased free T3 resin uptake), adrenal function (increased plasma cortisol, increased cortisol binding globulin, decreased dehydroepiandrosterone sulphate (DHEAS), and renal function (increased plasma creatinine and creatinine clearance)

− plasma levels of (carrier) proteins, such as corticosteroid-binding globulin and lipid/lipoprotein fractions

− parameters of carbohydrate metabolism

− parameters of coagulation and fibrinolysis

− decreased serum folate levels

Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, Aidulan 30/75 users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Aidulan 30/75 can be restarted 2 weeks following completion of treatment with this combination drug regimen.

4.6 Fertility, pregnancy and lactation

Pregnancy

Aidulan is not indicated during pregnancy.

If pregnancy occurs during medication with Aidulan, the preparation should be withdrawn immediately (see section 4.3).

Data on pregnancies exposed to gestodene are rather limited to permit conclusions concerning negative effects of gestodene on pregnancy, health of the foetus or neonate. Until now, no relevant epidemiological data are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

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. However, based on the hormonal action of the active compounds, an adverse effect of the active compounds on embryo-fetal development cannot be fully excluded.

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

Breastfeeding

Small amounts of contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement.

Lactation may be influenced by OCs as they may reduce the quantity and change the composition of breast milk.

The use of OCs should generally not be recommended until the nursing mother has completely weaned her child.

4.7 Effects on ability to drive and use machines

Aidulan 30/75 has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Use of COCs has been associated with:

− an increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism

− an increased risk of cervical intraepithelial neoplasia and cervical cancer

− an increased risk of being diagnosed with breast cancer

− an increased risk of benign hepatic neoplasm (e.g. focal nodular hyperplasia, hepatic adenoma).

These undesirable effects are described in more detail in Section 4.4

Frequency

Very common

≥1/10

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Rare

≥1/10,000 to <1/1,000

Very rare

<1/10,000

Not known

(cannot be estimated from available data

System organ ↓ class

Infections and infestations

vaginal infection (including candidiasis)

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

hepatocellular carcinoma, liver adenoma

Immune system disorders

anaphylactic/anaphylactoid reactions (including very rare cases of urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms)

systemic lupus erythematosus syndrome aggravated

Metabolism and nutrition disorders

fluid retention

increased or decreased appetite

glucose intolerance impaired

porphyria aggravated

Psychiatric disorders

mood altered, including depression, libido disorder

Nervous system disorders

headache, including migraines

nervousness

dizziness

chorea aggravated

Eye disorders

contact lens intolerance

optic neuritis*, retinal vascular thrombosis

Ear and labyrinth disorders

ear disorder

Vascular disorders

hypertension

VTE

ATE

varicose veins

Gastro-intestinal disorders

nausea, vomiting, abdominal pain

abdominal cramps, abdominal distension, diarrhoea

pancreatitis, colitis ischemic

inflammatory bowel disease (Crohn Disease, colitis ulcerative)

Hepato- biliary disorders

jaundice cholestatic

gallbladder disorder, including cholelithiasis**

hepato-cellular injury (e.g. hepatitis, hepatic function abnormal)

Skin and subcutaneous tissue disorders

acne

rash, chloasma (melasma) which may persist, hirsutism, alopecia

erythema nodosum

erythema multiforme

Renal and urinary disorders

haemolytic uremic syndrome

Reproductive system and breast disorders

metrorrhagia

breast pain, breast tenderness, breast enlargement, breast discharge, dysmen-orrhea, menstrual disorder, hypomen-orrhoea, change in menstrual flow, changes of the ectropion and secretion of the cervix, amenorrhea

General disorders and administration site conditions

irritability

Investigations

weight increased or decreased

blood pressure increased, lipids abnormal including hypertrigly-ceridaemia,

blood folate decreased***

*Optic neuritis may lead to partial or complete loss of vision.

** COCs may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women.

*** Serum folate levels may be depressed by COC therapy. This may be of clinical significance if the woman becomes pregnant shortly after discontinuing COCs.

The following serious adverse events have been reported in women using COCs, see sections 4.3 and 4.4.

− Cervical cancer

− Liver tumours

− Skin and subcutaneous disorders: chloasma.

The frequency of diagnosis of breast cancer is very slightly increased among COC-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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Acute intoxication by high oral doses of the product administered to young children did not lead to any serious symptoms of diseases. Symptoms of oral contraceptive overdosage in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment of overdose, if necessary, is directed to the symptoms.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hormonal contraceptives for systemic use, progestogens and estrogens, fixed combinations, ATC code: G03A A10

Combined oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of action is the inhibition of ovulation, other mechanisms including changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation) support the contraceptive effect.

5.2 Pharmacokinetic properties

Gestodene

Absorption

Orally administered gestodene is rapidly and completely absorbed. Peak serum concentration of approximately 2-4 ng/ml is reached approximately 1 hour after single dose. Bioavailability is approximately 99%.

Distribution

Gestodene is bound to serum albumin and SHBG. Only 1-2% of the total serum concentration of the substance is free steroid, 50-75% is specifically bound to SHBG. The ethinylestradiol induced increase in SHBG affects the amount of gestodene bound to serum proteins, which causes an increase in the SHBG-bound fraction and a decrease in the albumin-bound fraction. The apparent volume of distribution of gestodene is 0.7-1.4 l/kg.

Biotransformation

Gestodene is completely metabolised via the known steroid pathways.

Mean metabolic clearance rate from serum is 0.8-1.0 ml/min/kg.

Elimination

The serum levels of gestodene fall into two phases. The final disposition phase is characterised by a half-life of 12-20 hours. Only gestodene metabolites are excreted, with a rate between urine and bile of 6:4. The half-life for metabolite excretion is approximately 1 day.

Steady-state

The pharmacokinetics of gestodene is influenced by SHBG levels, which rise up to approximately threefold at concomitant administration of ethinylestradiol. After daily intake the serum levels increase up to approximately three- to fourfold and reach steady-state level within the second half of the treatment cycle.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentration of approximately 30-80 pg/ml is reached within 1-2 hours. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%.

Distribution

Ethinylestradiol is strongly but not specifically bound to serum albumin (approximately 98.5%) and leads to an increase in serum concentration of SHBG. An apparent volume of distribution of 5-18 l/kg was shown.

Biotransformation

Ethinylestradiol is primarily metabolised by aromatic hydroxylation, but a large number of hydroxylated and methylated metabolites are produced, and these are present as free metabolites and as conjugates with glucuronides and sulphate. The metabolic clearance rate is around 5-13 ml/min/kg.

Elimination

Ethinylestradiol serum levels fall in two phases, the final disposition phase is characterised by a half-life of approximately 16-24 hours. Only metabolites are excreted, this takes place with a rate between urine and bile of 2:3. The half-life for excretion of metabolites is approximately 1 day.

Steady-state

Steady-state condition is reached after 3-4 days during which the serum level for the substance is 20% higher than after a single dose.

5.3 Preclinical safety data

Preclinical studies (general toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction) have not revealed other effects than those which can be explained based on the known hormone profile of ethinylestradiol and gestodene.

It should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate

Maize starch

Sodium calcium edetate dihydrate

Povidone K30

Magnesium stearate

Opadry white coating:

Hypromellose

Titanium Dioxide (E171)

Macrogol 400

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

For PVC/ Aclar blister packs: 2 years

For PVC blister packs: 3 years

6.4 Special precautions for storage

Do not store above 25° C. Store in the original package.

6.5 Nature and contents of container

Blisters of PVC/Al foil in aluminium pouch, PVC/Aclar/Al foil in aluminium pouch, PVC/Aclar/Al foil with desiccant in aluminium pouch.

Presentation:

Blisters containing 21 tablets in pack sizes of 21 (1x 21), 63 (3x21), 126 (6x 21) and 273 (13 x 21) tablets*.

* Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Lupin Healthcare (UK) Limited

The Urban Building, 2nd floor,

3-9 Albert Street, Slough, Berkshire,

SL1 2BE, United Kingdom.

8. Marketing authorisation number(s)

PL 35507/0117

9. Date of first authorisation/renewal of the authorisation

03/12/2013

10. Date of revision of the text

29/11/2018.