Ioa - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

IOA 2.5 mg/1.5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

White active film-coated tablets: Each film-coated tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate).

Yellow placebo film-coated tablets: The tablet does not contain active substances.

Excipients with known effect :

Each white active film-coated tablet contains 57.71 mg of lactose m

Each yellow placebo film-coated tablet contains 61.76 mg of lactose

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Active film-coated tablets: white, round and coded ‘ne’ on both sides.

4.1 Therapeutic indications

4. CLINICAL PARTICULARS

Placebo film-coated tablets: yellow, round and cod on both sides.

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

4. 2 Posology and method of administration

'A

Posology

One tablet is to be taken daily for 28 consecutive days. Each pack starts with 24 white active tablets, followed by 4 yellow placebo tablets. A subsequent pack is started immediately after finishing the previous pack, without a break in daily tablet intake and irrespective of presence or absence of withdrawal bleeding. Withdrawal bleeding usually starts on day 2–3 after intake of the last white tablet and may not have finished before the next pack is started. See ‘Cycle control’ in section 4.4.

Special populations

Renal impairment

Although data in renal impaired patients are not available, renal impairment is unlikely to affect the elimination of nomegestrol acetate and estradiol.

Hepatic impairment

No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism of steroid hormones might be impaired in patients with severe hepatic disease, the use of IOA in these women is not indicated as long as liver function values have not returned to normal (see section 4.3).

Method of administration

Oral use.

How to take IOA

Tablets must be taken every day at about the same time without regard to meals. Tablets should taken with some liquid as needed, and in the order as directed on the blister. Stickers marked wi 7 days of the week are provided. The woman should choose the sticker that starts with the day she begins taking the tablets and stick it on the blister.

How to start IOA

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 da bleeding). When doing so, no additional contraceptive measures are necessary.

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

The woman should start with IOA preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using IOA preferably on the day of removal, but at the latest when the next application would have been due.

Changing from a progestogen-only-method (minipill, implant, injectable) or from a hormone-medicated Intra Uterine System (IUS)

The woman may switch any day from the minipill and IOA should be started on the next day. An implant or IUS may be removed any day, and IOA should be started on the day of its removal. When changing from an injectable, IOA should be started on the day when the next injection would have been due. In all of these cases, the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active tablet-taking.

Following first-trimester abortion

The woman may start immediately. When doing so, no additional contraceptive measures are necessary.

Following delivery or second-trimester abortion

Women should be advised to start between day 21 and 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.

For breast-feeding women see section 4.6.

magement of missed tablets

The following advice only refers to missed white active tablets:

If the woman is less than 12 hours late in taking any active tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.

If she is more than 12 hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

• • 7 days of uninterrupted ‘white active tablet’-taking are required to attain adequate suppression

of the hypothalamic-pituitary-ovarian-axis.

• • The more ‘white active tablets’ are missed and the closer the missed tablets are to the 4 yellow placebo tablets, the higher the risk of a pregnancy.

Day 1–7

The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered.

Day 8–17

The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.

Day 18–24

The risk of reduced reliability is imminent because of the forthcoming placebo tablet phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, she should follow the first of these two options and use extra precautions for the next 7 days as well.

• 1. The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time until the active tablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days.

• 2. The woman may also be advised to discontinue active tablet-taking from the current blister pack. She should then take placebo tablets from the last row for up to 4 days, including the days she missed tablets, and subsequently continue with the next blister pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet phase, the possibility of a pregnancy should be considered.

Yellow placebo tablets missed

Contraceptive protection is not reduced. Yellow tablets from the last (4th) row of the blister can be disregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging the placebo tablet phase.

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbance (e.g., vomiting or diarrhoea), absorption of the active substances may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3–4 hours after white tablet-taking, a new tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in section 4.2 „Management of missed tablets“, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra white tablet(s) from another pack.

How to shi ft periods or how to delay a period

To delay a period the woman should continue with another blister pack of IOA without taking the yellow placebo tablets from her current pack. The extension can be carried on for as long as wished until the end of the white active tablets in the second pack. Regular intake of IOA is then resumed after the yellow placebo tablets have been taken of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting.

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 yellow placebo tablet phase with a maximum of 4 days. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and may experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

4.3 Contraindications

Combined hormonal contraceptives (CHCs) should not be used in the following conditions. As no epidemiological data are yet available with 17p—estradiol containing CHCs, the contraindications for ethinylestradiol containing CHCs are considered applicable to the use of IOA. Should any of the conditions appear for the first time during IOA use, the medicinal product should 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 (AT

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 hypertriglyce­ridaemia.

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.

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 IOA 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 IOA should be discontinued. All data presented below are based upon epidemiological data obtained with CHCs containing ethinylestradiol. IOA contains 17p-estradiol. As no epidemiological data are yet available with estradiol containing-CHCs, the warnings are considered applicable to the use of IOA.

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 IOA compares with these lower risk products. The decision to use any product other than one known to have the lowest VTE risk 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 (<50 ^g ethiny’estradiol) combined hormonal contraceptives have found that out of 10,000 women between 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 6will develop a VTE in one year.
• • It is not yet known how the risk of VTE with CHCs that contain nomegestrol acetate in combination with estradiol compares with the risk with low dose levonorgestrel-containing CHCs.
• • 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.
• • 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).

IOA 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).

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). IOA 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

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 a 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). No epidemiological data on the risk of cervical cancer in users of IOA are available.
• • With the use of the higher-dosed COCs (50 p.g ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to 17p-estradiol-containing COCs remai is to be confirmed.
• • A meta-analysis from 54 epidemiological studies reported that there is a slightly incr

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. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. 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.

• • 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 intraabdominal haemorrhages. Therefore, 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

pancreatitis when using COCs.

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. A 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 suspend the intake of the tablets 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 pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic 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 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 low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking a COC, especially in the first months of use.

Worsening of depression, Crohn’s disease and ulcerative colitis 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.

• • Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions

Influence of other medicinal products on IOA

Interactions between oral contraceptives and enzyme-inducing medicinal products may lead to breakthrough bleeding and even contraceptive failure.

Examples of active substances that induce hepatic enzymes and thus result in increased clearance of sex hormones are: phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, and medicinal products or herbal preparations containing St. John’s wort, and, to a lesser extent, oxcarbazepine, topiramate, felbamate, and griseofulvin. 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.

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

Medicinal product interaction studies were not performed with IOA, but two studies with rifampicin and ketoconazole, respectively, were performed with a higher dosed nomegestrol acetate-estradiol combination (nomegestrol acetate 3.75 mg + 1.5 mg estradiol) in post-menopausal women.

Concomitant use of rifampicin decreases the AUC0-v of nomegestrc l acetate by 95 % and increases the AUC0-tlast of estradiol by 25 %. Concomitant use of ketoconazole (200 mg single dose) does not modify estradiol metabolism whereas increases in the peak concentration (85 %) and AUC0-v (115 %) of nomegestrol acetate were observed, which were of no clinical relevance. Similar conclusions are expected in women of childbearing potential.

Influence of IOA on other medicinal products

Oral contraceptives may affect the metabolism of other medicinal products. Special attention should be paid to the interaction with lamotrigine.

Laboratory tests

fluence the results of certain laboratory tests, including

biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.6 Fertility, pregnancy and lactation

Pregnancy

IOA is not indicated during pregnancy.

If pregnancy occurs while taking IOA, further intake should be stopped. Most epidemiological studies have revealed neither an increased risk of birth defects in infants born to women who used ethinylestradiol-containing COCs prior to pregnancy, nor a teratogenic effect when ethinylestradiol-containing COCs were taken inadvertently during early pregnancy.

Clinical data on a limited number of exposed pregnancies indicate no adverse effect of IOA on the foetus or neonate.

In animal studies, reproductive toxicity has been observed with the nomegestrol acetate / estradiol combination (see preclinical safety data in section 5.3).

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

Breast-feeding

Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the breast milk, but there is no evidence that this adversely affects infant health.

Breastfeeding may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should not be recommended until the nursing mother has completely weaned her child and an alternative contraceptive method should be proposed to women wishing to breastfeed.

Fertility

IOA is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.

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 with IOA. However, no effects on ability to drive and use machines have been observed in users of COCs.

4.8 Undesirable effectsuate safety of IOA. In total

Six multi-centre clinical trials of up to one year duration were u 3,434 women, aged 18–50, were enrolled and completed 33,828

Tabulated summary of adverse reactions

Possibly related adverse reactions that have been reported in clinical trials or during postmarketing use with IOA are listed in the table below.

All adverse reactions 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 (> 1/10,000 to < 1/1,000).

1The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

In addition to the above mentioned adverse reactions, hypersensitivity reactions have been reported in IOA users (frequency unknown).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued mom. >ring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

nCn

Multiple doses up to five times the daily dose of IOA and single doses up to 40 times the daily dose of nomegestrol acetate alone have been used in women without safety concern. On the basis of general experience with combined oral contraceptives, symptoms that may occur are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Nomegestrol acetate is a highly selective progestogen derived from the naturally occurring steroid hormone, progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptor and has an anti-gonadotropic activity, a progesterone receptor-mediated anti-estrogenic activity, a moderate anti-androgenic activity, and is devoid of any estrogenic, androgenic, glucocorticoid or mineralocorticoid activity.

The estrogen contained in IOA is 17p-estradiol, a natural estrogen identical to the endogenous human 17P-estradiol.

The contraceptive effect of IOA 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 cervical secretion.

In two randomized, open-label, comparative efficacy-safety trials, more than 3,200 women have been treated for up to 13 consecutive cycles with IOA and more than 1,000 women with drospirenone 3 mg – ethinylestradiol 30 ^g (21/7 regimen).

In the IOA group, acne was reported by 15.4 % of the women (versus 7.9 % in the comparator group), weight increased was reported by 8.6 % of the women (versus 5.7 % in the comparator group), and abnormal withdrawal bleeding (predominantly absence of withdrawal bleeding) was reported by 10.5 % of the women (versus 0.5 % in the comparator group).

In the clinical trial performed with IOA in the European Union the following Pearl Indices for the age class 18–35 years were calculated:

Method failure: 0.40 (upper limit 95 % confidence interval 1.03)

Method and user failure: 0.38 (upper limit 95 % confidence interval 0.97)

In the clinical trial performed with IOA in the United States the following Pearl Indices for the age class 18–35 years were calculated:

Method failure: 1.22 (upper limit 95 % confidence interval 2.18)

Method and user failure: 1.16 (upper limit 95 % confidence interval 2.08)

In a randomized, open label trial, 32 women were treated for 6 cycles with IOA.

After discontinuation of IOA, return to ovulation in the first 28 days after last tablet intake was observed in 79 % of the women.

Endometrial histology was investigated in a subgroup of women (n=32) in one clinical study after 13 cycles of treatment. There were no abnormal results.

5.2 Pharmacokinetic properties

diatric population

data on efficacy and safety are available in adolescents below 18 years. Available pharmacokinetic ata are described in section 5.2.

Nomegestrol acetate

Absorption

Orally administered nomegestrol acetate is rapidly absorbed.

Maximum plasma concentrations of nomegestrol acetate of about 7 ng/ml are reached at 2 h after single administration. The absolute bioavailability of nomegestrol acetate after a single dose is 63 %. No clinically relevant effect of food was observed on the bioavailability of nomegestrol acetate.

Distribution

Nomegestrol acetate is extensively bound to albumin (97–98 %), but does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). The apparent volume of distribution of nomegestrol acetate at steady-state is 1,645 ± 576 l.

Biotransformation

Nomegestrol acetate is metabolized into several inactive hydroxylated metabolites by liver cytochrome P450 enzymes, mainly CYP3A4 and CYP3A5 with possible contribution of CYP2C19 and CYP2C8. Nomegestrol acetate and its hydroxylated metabolites undergo extensive phase 2 metabolism to form glucuronide- and sulphate conjugates. The apparent clearance at steady state is 26 l/h.

Elimination

The elimination half-life (t1/2) is 46 h (ranging from 28–83 h) at steady state. Th of metabolites was not determined.

Nomegestrol acetate is excreted via urine and feces. Approximately 80 % urine and feces within 4 days. Excretion of nomegestrol acetate was ne amounts excreted were higher in feces than in urine.

Linearity

Dose-linearity was observed in the range 0.625–5 mg (assessed in fertile and post-menopausal women).

Steady-state conditions

The pharmacokinetics of nomegestrol acetate are not influenced by SHBG.

Steady-state is achieved after 5 days. Maximum plasma concentrations of nomegestrol acetate of about 12 ng/ml are reached 1.5 h after dosing. Average steady state plasma concentrations are 4 ng/ml.

Drug drug interactions

Nomegestrol acetate causes in vitro no notable induction or inhibition of any cytochrome P450 enzymes and has no clinically relevant interaction with the P-gp transporter.

Absorption

Estradiol is subject to a substantial first-pass effect after oral administration. The absolute bioavailability is about 1 %. No clinically relevant effect of food was observed on the bioavailability of estradiol.

Distribution

The distribution of exogenous and endogenous estradiol is similar. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37 %) and to albumin (61 %), while only approximately

Oral exogenous estradiol is extensively metabolized. The metabolism of exogenous and endogenous estradiol is similar. Estradiol is rapidly transformed in the gut and the liver in several metabolites, mainly estrone, which are subsequently conjugated and undergo entero-hepatic circulation. There is a dynamic equilibrium between estradiol, estrone and estrone-Sulfate due to various enzymatic activities including estradiol-dehydrogenases, sulfotransferases and aryl sulfatases. Oxidation of estrone and estradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9.

Elimination

Estradiol is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation, a large circulating pool of estrogen sulfates and glucuronides is present. This results in a highly variable baseline-corrected elimination half-life of estradiol, which is calculated to be 3.6 ± 1.5 h, after intravenous administration.

Steady-state conditions

Maximum serum concentrations of estradiol are about 90 pg/ml and are reached 6 h after dosing.

Average serum concentrations are 50 pg/ml and these estradiol levels correspond with the early and late phase of a woman’s menstru­al cycle.

Special populations

Paediatric population

The pharmacokinetics of nomegestrol acetate (primary objective) after single oral dosing of IOA in healthy postmenarcheal female adolescents and adult subjects were similar. However, after single oral dosing, for the estradiol component (secondary objective), the exposure was 36 % lower in adolescents versus adult subjects. The clinical relevance of this result is unknown.

Effect of renal impairment

No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of IOA.

Effect of hepatic impairment

No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of IOA. However, steroid hormones may be poorly metabolized in women with impaired liver function.

Ethnic groups

No formal studies were performed to assess pharmacokinetics in ethnic groups.

5.3 Preclinical safety data

acetate is not genotoxic.

However, it must be borne in mind that sex steroids can promote the growth of certain hormonedependent tissues and tumours.

6. PHARMACEUTICAL PARTICULARS

♦. <L >

6.1 List of excipients

Lactose monohydrate

Cellulose, microcrystalline (E460)

Crospovidone (E1201)

Talc (E553b)

Magnesium stearate (E572)

Silica, colloidal anhydrous

Tablet coating (white active film-coated tablets)

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

PVC/aluminium blister containing 28 film-coated tablets (24 white film-coated tablets and 4 yellow film-coated tablets).

Pack sizes: 28 and 84 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

7. MARKETING AUTHORISATION HOLDER

9.  DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION