SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Maexeni 150/30 microgram film coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient(s) with known effect:

Each tablet contains 58.32 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Yellow, round, biconvex, film-coated tablet, debossed with “LE4” on one side and plain on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Oral contraception.

4.2    Posology and method of administration

How to use Maexeni tablets

Tablets must be taken orally in the order directed on the blister package at about the same time every day, with some liquid if necessary. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval, during which time a withdrawal bleed usually occurs. The bleeding usually starts within 2 to 3 days after the last tablet and may not end before the next pack is started.

How to start the use of Maexeni tablets

No preceding hormonal contraceptive use [in the past month]

Tablet-taking is started on day 1 of the woman's natural cycle (= the first day of her menstrual bleeding).

Starting on days 2-5 is allowed but in that case an additional barrier method is recommended for the first 7 days of the first cycle

• Changing from another combined hormonal contraceptive (COC, vaginal ring, transdermal patch)

The use of Maexeni tablets is preferably started on the day after the last active tablet of the previous COC (or after removal of the ring or patch), but at the latest on the day following the usual tablet-free (ring-free, patch-free) break or the last placebo tablet of the previous hormonal contraceptive.

• Changing from a progestogen-only method (oralpill, injection, implant) or intrauterine system (IUS)

The woman can switch to Maexeni tablets any day from the minipill (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 use an additional barrier method for the first 7 days of tablet-taking.

• Following first-trimester abortion

The use of the tablets can start immediately. In such a case, no other contraceptive measures are needed.

• Following delivery or second-trimester abortion

For breast-feeding, see section 4.6 Fertility, pregnancy and lactation.

The use of the tablets is started 21 to 28 days after delivery or second-trimester abortion. When starting later, an additional barrier method must be used for the first 7 days of tablet-taking. If the woman has already had sexual intercourse, pregnancy must be excluded before the actual start of COC use or the woman has to wait for her next menstrual period.

Missed tablets

Maexeni contains a very low dose of both hormones, and, as a consequence, the contraceptive efficacy margin is small, if a pill is missed. If the woman is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and take the next tablets at the usual time.

If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The following two basic rules apply in cases where tablets have been missed:

1.    Tablet-taking must never be discontinued for longer than 7 days.

2.    Adequate suppression of the hypothalamic-pituitary-ovarian axis requires 7 days of uninterrupted tablet-taking.

Accordingly, the following advice can be given for daily practice:

Week 1

The woman 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 the next tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If the woman has had sexual intercourse in the 7 days before missing the tablet, the possibility of a pregnancy must be considered. The more tablets have been missed and the closer they are to the regular tablet-free break, the higher the risk of pregnancy.

Week 2

The woman 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 the next 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. If she has not taken the tablets correctly or has missed more than one tablet, she should be advised to use extra contraceptive precautions for the next 7 days.

Week 3

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

1.    The woman 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 the next tablets at her usual time. The next pack is started as soon as the current pack is finished, i.e. there is no tablet-free break. There will probably be no withdrawal bleed until the end of the second pack, but the woman may experience spotting or breakthrough bleeding on tablet-taking days.

2.    It is also possible to stop taking tablets from the current pack. The woman must then have a tablet-free break of 7 days, including the days she missed tablets, and then continue with the next pack.

If the woman misses several tablets and has no withdrawal bleed during the first normal tablet-free break, the possibility of a pregnancy must be considered.

Advice in case of gastro-intestinal disturbances

In case of severe gastrointestinal symptoms, absorption of the active ingredients may not be complete and additional contraceptive measures should be taken.

If vomiting or severe diarrhea occurs within 3-4 hours after taking a tablet, the woman should apply the advice given for missed tablets. If the woman does not want to change her normal tablet schedule, she has to take the extra tablet(s) from another pack.

How to change the starting day of a period or to delay a period

To delay a period the woman should start a new pack immediately after finishing the current pack without any break. Periods can be delayed as long as wished, but no later till the end of the second pack. During this time the woman may experience breakthrough-bleeding or spotting. Regular intake of Maexeni is then resumed after the usual 7-day tablet-free break.

If the woman wants to change the starting day or her periods to another day of the week, she can be advised to shorten her next tablet-free break by as many days as she likes. The shorter the break, the higher the risk that there will be no withdrawal bleed and that the woman will experience breakthrough-bleeding and spotting during the second pack (just as when delaying a period).

4.3 Contraindications

Combined oral contraceptives (COCs) are not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during COC use, the product should be stopped immediately.

•    Venous thrombosis present or in history (deep venous thrombosis, pulmonary embolism)

•    Arterial thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris and transient ischaemic attack)

•    Cerebrovascular accident present or in history

•    The presence of a severe or multiple risk factor(s) for arterial thrombosis:

•    Diabetes mellitus with vascular symptoms

•    Severe hypertension

•    Severe dyslipoproteinemia

•    Hereditary or acquired predisposition for venous or arterial thrombosis, such as APC-resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)

•    History of migraine with focal neurological symptoms

•    Pancreatitis or a history of such a condition, if associated with severe hypertriglyceridemia

•    Severe hepatic disease, current orprevious, 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

•    Amenorrhea of unknown cause.

Hypersensitivity to the active substances, levonorgestrel and ethinylestradiol or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Medical Examination

Warnings

If any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether its use should be discontinued.

• Vascular disorders

Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 pg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 woman-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 woman-years for non-users.

The use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use.

The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 12% of cases.

The overall absolute risk (incidence) of VTE for levonorgestrel containing combined oral contraceptives with 30 pg ethinylestradiol is approximately 20 cases per 100,000 women-years of use.

Epidemiological studies have also associated the use of combined COCs with an increased risk for myocardial infarction, transient ischaemic attack and for stroke.

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries, in contraceptive pill users. There is no consensus as to whether the occurrence of these events is associated with the use of hormonal contraceptives.

Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include:

•    unusual unilateral leg pain and / or swelling

•    sudden severe pain in the chest, whether or not it radiates to the left arm

•    sudden breathlessness

•    sudden onset of coughing

•    any unusual, severe, prolonged headache

•    first occurrence or worsening of migraine

•    sudden partial or complete loss of vision

•    diplopia

•    slurred speech or aphasia

•    vertigo

•    collapse with or without focal seizure

•    weakness or very marked numbness suddenly affecting one side or one part of the body

•    motor disturbances

•    ‘acute’ abdomen.

Occurence of one or more of these symptoms may be a reason for immediate discontinuation of Maexeni.

The risk for venous thromboembolic complications in COC users increases with:

•    increasing age

•    a positive family history (venous thromboembolism ever in a sibling or parent atrelatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use

•    prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered if the pills have not been discontinued in advance

•    obesity (body mass index over 30 kg/m²)

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

The risk of arterial thromboembolic complications or of a cerebrovascular accident in COC users increases with:

•    increasing age

•    smoking (women over 35 years should be strongly advised not to smoke if they wish to use an COC)

•    dyslipoproteinaemia

•    hypertension

•    migraine, especially migraine with focal neurological symptoms

•    valvular heart disease

•    atrial fibrillation.

The presence of one serious risk factor or multiple risk factors for venous or arterial disease, respectively, can also constitute a contra-indication. The possibility of anticoagulant therapy should also be taken into account. COC users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

The increased risk of thromboembolism in the puerperium must be considered (see section 4.6 Fertility, pregnancy and lactation).

Other medical conditions which have been associated with adverse vascular events include diabetes mellitus, systemic lupus erythematosus, haemolytic uremic syndrome and chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis).

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

• Tumours

An increased risk of cervical cancer in long-term users of COCs 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 of 54 epidemiological studies showed 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.

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

• Other conditions

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when 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. A systemiatic relationship between COC use and clinical hypertension has not been established.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 during 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, depressive mood.

In women with hereditary angioedema exogenous oestrogens may induce or exacerbate symptoms of angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until the liver function values return to normal. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus which previously occurred during pregnancy or previous use of sex steroids necessitates 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. However, diabetic women should be carefully monitored, 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.

Maexeni contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.

Medical examination/consultation

Prior to the initiation or reinstitution of Maexeni 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 Contraindications) and warnings (see section 4.4 Special Warnings and special precautions for use). 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 transmissible diseases.

Reduced efficacy

The efficacy of COCs may be reduced in the event of e.g. missed tablets, vomiting or diarrhea or concomitant medication.

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 period of about three cycles. In users of COC’s with the same active substances, any bleeding (spotting and/or breakthrough bleeding) was reported by more than 50% during the first 6 months of use.

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

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

4.5 Interaction with other medicinal products and other forms of interaction

Interactions

Hepatic enzyme inducers

Drugs which induce hepatic enzymes (especially cytochrome P450 3A4) increase the metabolism of contraceptive steroids and hence may result in breakthrough bleeding and pregnancy. The following have been shown to have clinically important interactions with COCs:

Antiretroviral agents

•    ritonavir;

•    nelfinavir;

•    nevirapine.

Anticonvulsants

•    barbiturates (including phenobarbitone);

•    primidone;

•    phenytoin;-

•    carbamazepine;

•    oxcarbazepine;

•    topiramate.

Antibiotics/antifungals

•    griseofulvin;

•    rifampacin.

Herbal remedies

•    St John's wort (Hypericum perforatum)

Managing interactions with hepatic enzyme inducers

Since interactions of enzyme inducers, including the antibiotics rifampicin and griseofulvin, with oral contraceptives may lead to breakthrough bleeding and/or contraceptive failure the following precautions are recommended:

Women on short term treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. With microsomal enzyme-inducing drugs, such as rifampicin and griseofulvin, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.

For women receiving long-term therapy with hepatic enzyme inducers, another method of contraception should be used.

Non-enzyme inducing antibiotics

Some clinical reports suggest that enterohepatic circulation of oestrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).

Managing interactions with non-enzyme inducing antibiotics

Since interactions of some antibiotics with oral contraceptives may lead to breakthrough bleeding and/or contraceptive failure the following precautions are recommended:

Women on short term treatment with antibiotics (except rifampicin and griseofulvin) should temporarily use a barrier method in addition to the COC or choose another method of contraception. If the barrier method is chosen it should be used until 7 days after discontinuation of the antibiotics. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.

Effects on other drugs

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

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

Laboratory tests

The use of oral contraceptives may influence the results of certain laboratory tests including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Laboratory staff should therefore be informed about oral contraceptive use when laboratory tests are requested.

4.6 Fertility, pregnancy and lactation

Pregnancy

Maexeni is not indicated during pregnancy. If pregnancy occurs during treatment with Maexeni, further intake must be stopped. However, 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 early pregnancy.

Breast-feeding

The use of levonorgestrel / ethinylestradiol during lactation may lead to a reduction in the volume of milk produced and to a change in its composition. Minute amounts of the active substances are excreted with the milk. These amounts may affect the child particularly in the first 6 weeks post-partum. Mothers who are breast-feeding may be advised instead to use another method of contraception.

4.7 Effects on ability to drive and use machines

Ethinylestradiol / levonorgestrel have no effects or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

All adverse drug reactions are listed by system organ class and frequency:

Very common > 1/10), Common ( 1/100, < 1/10), Uncommon ( 1/1000, < 1/100), Rare ( 1/10,000, < 1/1000), Very Rare (< 1/10,000), not known (cannot be estimated from the available data).

The following adverse events have been reported during use of ethinylestradiol / levonorgestrel:

System Organ Class	Adverse events reported in clinical trials			Adverse events reported post marketing
	Common	Uncommon	Rare
	(> 1/100)	(> 1/1000, <1/100)	(< 1/1000)
Eye disorders			contact lens intolerance
Gastrointestinal disorders	nausea, abdominal pain	vomiting, diarrhea
Immune system disorders			hypersensitivity	exacerbation of hereditary angioedema
Investigations	weight		weight decreased

	increased
Metabolism and nutrition disorders		fluid retention		Hypertriglyceridemia
Nervous system disorders	headache	migraine		exacerbation of chorea
Gastrointestinal disorders				Crohn's disease, ulcerative colitis
Hepatobiliary disorders				liver function disturbances
Psychiatric disorders	depressed mood, mood altered	libido decreased	libido increased
Reproductive system and breast disorders	breast pain, breast tenderness	breast hypertrophy	vaginal discharge, breast discharge	reduced menstrual flow, spotting, breakthrough bleeding and missed withdrawal bleeding, post pill amenorrhoea
Skin and subcutaneous tissue disorders		rash, urticaria	erythema nodosum, erythema multiforme	chloasma

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 'Special warnings and precautions for use':

•    Venous thromboembolic disorders

•    Arterial thromboembolic disorders

•    Strokes (e.g. transient ischemic attack, ischemic stroke, haemorrhagic stroke)

•    Hypertension

•    Liver tumours (benign and malignant)

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 'Contraindications' and 4.4 'Special warnings and precautions for use.

Conditions reported to deteriorate with pregnancy or previous COC use Jaundice and/or pruritus related to cholestasis; gallstone formation; systemic lupus erythematosus; herpes gestationis; otosclerosis-related hearing loss; sickle cell anaemia; renal dysfunction; hereditary angioedema; porphyria; cervical cancer.

Changes in glucose tolerance or effect on peripheral insulin resistance have been reported in women using COCs (see section 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: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There have been no reports of serious effects from overdose. Overdosage may cause nausea, vomiting and, in females, withdrawal bleeding.

There are no specific antidotes and treatment should be symptomatic.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: progestrogens and estrogens, fixed combinations, ATC code: G03AA07

Maexeni is an oestrogen-progestogen combination which acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinising hormone, the inspissation of cervical mucus producing a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.

5.2 Pharmacokinetic properties

Levonorgestrel

Levonorgestrel is absorbed quickly and completely. Maximum active substance levels of approx 3 ng/ml were reached in serum just one hour after ingestion of levonorgestrel / ethinylestradiol tablets. The serum concentrations subsequently fell in 2 phases with half-lives of around 0.5 hours and 20 hours. The metabolic clearance rate from plasma is approx. 1.5 ml/min/kg.

Levonorgestrel is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day and in almost equal proportions via the kidney and bile. Biotransformation takes place via the familiar pathways of steroid metabolism. There are no known pharmacologically active products of metabolism.

Levonorgestrel is bound to serum albumin and SHBG. Only around 1.5% of the respective total concentration is present in unbound form, while approx. 65% is bound to SHBG. The relative proportions (free, albumin-bound, SHBG-bound) depend on the concentration of SHBG. After induction of the binding protein, the portion bound to SHBG increases, while the free portion and that bound to albumin decreases.

After daily repeated ingestion, levonorgestrel accumulates by about the factor 2. A steady state is reached during the second half of the treatment cycle. The pharmacokinetics of levonorgestrel are dependent on the concentration of SHBG in plasma. Under treatment with Microgynon, an increase in the levels of SHBG effect a concomitant increase in the specific binding capacity and therefore also an increase in levonorgestrel serum levels.

The levonorgestrel serum levels do not change any further after 1 - 3 cycles of use owing to the fact that SHBG induction is concluded. Compared to a single administration, 3 - 4 fold higher levonorgestrel serum levels are reached in the steady state.

The absolute bioavailability of levonorgestrel amounts to almost 100%.

Approx. 0.1% of the maternal dose can be passed on to a baby with the breast milk.

Ethinylestradiol

Orally administered ethinylestradiol is absorbed quickly and completely. Ingestion of levonorgestrel / ethinylestradiol tablets leads to maximum plasma levels of approx. 100 pg/ml after 1 - 2 hours. The substance concentration then falls in 2 phases for which half-lives of around 1 - 2 hours and about 20 hours have been determined. For technical reasons, these data can only be calculated at higher dosages.

An imaginary distribution volume of around 5 l/kg and a metabolic clearance rate from plasma of approx. 5 ml/min/kg have been determined for ethinylestradiol. Ethinylestradiol is bound non-specifically to serum albumin to the extent of 98%.

Ethinylestradiol is metabolised even during its absorption phase and during its first liver transit, leading to reduced and individually varying oral bioavailability. Ethinylestradiol is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day. The excretion ratio is 40 (urine): 60 (bile).

Because of the half-life of the terminal elimination phase from plasma, a steady state characterised by a 30 - 40% higher plasma substance level becomes established after approx. 5 - 6 daily administrations.

The absolute bioavailability of ethinylestradiol is subject to considerable interindividual variations. After oral ingestion, it amounts to around 40 - 60% of the dose.

In women with fully established lactation, around 0.02% of the maternal dose can be passed on to the baby with the breast milk.

Other drugs can have a negative or positive effect on the systemic availability of ethinylestradiol. No interaction with vitamin C takes place. On continuous use, ethinylestradiol induces the hepatic synthesis of CBG and SHBG, the extent of SHBG induction being dependent on the type and dose of the simultaneously administered progestogen.

5.3 Preclinical safety data

Non-clinical 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 levonorgestrel.

However, 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

Tablet core:

Lactose anhydrous Microcrystalline cellulose Povidone K30 Croscarmellose sodium Magnesium stearate (E470b)

Film-coating:

Hypromellose (HPMC, E464) Titanium dioxide (E171) Macrogol 400 (PEG 400)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months for the Al/PVC/Aclar blister in an aluminium laminated pouch 18 months for the Al/PVC/Aclar blister (i.e. without an aluminium laminated pouch)

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Maexeni film coated tablets are packed in an aluminium foil/clear transparent PVC blister; packed inside an aluminium laminated pouch or an aluminium foil/clear transparent PVC/Aclar blister, which may be packed inside an aluminium laminated pouch and further packed in to cartons.

Each blister contains 21 tablets.

Maexeni is available in packs of 21 (1x21), 63 (3x21), 126 (6x21) and 273 (13x21) tablets.

Not all pack types or pack sizes may be marketed.

6.6 Special precautions for disposal

No specific requirements.

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

7 MARKETING AUTHORISATION HOLDER

Lupin (Europe) Limited

Victoria Court

Bexton Road

Knutsford

Cheshire

WA16 0PF

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 35507/0037

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/12/2013

10    DATE OF REVISION OF THE TEXT

10/06/2014