1 NAME OF THE MEDICINAL PRODUCT

Elevin 30 micrograms/150 micrograms film-coated tablets

Leandra 30micrograms/150 micrograms film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

One film-coated tablet contains 54.84 mg lactose monohydrate For a full list of excipients see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet

Brownish, round convex, film-coated tablets

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Oral contraception.

4.2 Posology and method of administration

Route of administration: oral use

How to take Elevin

The tablets must be taken every day at about the same time, if necessary with a little liquid, in the order shown on the blister pack. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval, during which time a withdrawal bleed usually occurs. This usually starts on day 2-3 after the last tablet and may not have finished before the next pack is started.

How to start Elevin .•No preceding hormonal contraceptive use (in the past month)

Tablet-taking has to start on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual bleeding).

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

The woman should start with Elevin 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 Elevin preferably on the day of removal, but at the latest when the next application would have been due.

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

The woman may switch any day from the progestogen-only pill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

• Following first-trimester abortion

The woman may start immediately. When doing so, she need not take additional contraceptive measures.

• Following delivery or second-trimester abortion

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

For breastfeeding women see section 4.6.

Management of missed tablets

If the user 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 should take further tablets at the usual time.

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

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

2.    7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

Accordingly the following advice can be given in daily practice:

• Week 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. 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. The more tablets are missed and the closer they are to the regular tablet-free interval, the higher the risk of a pregnancy.

• Week 2

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.

Week 3

The risk of reduced reliability is imminent because of the forthcoming 7-day tablet-free interval. 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. The next blister pack must be started as soon as the current blister pack is finished, i.e., no gap should be left between packs. The user is unlikely to have a withdrawal bleed until the end 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 tablet-taking from the current blister pack. She should then have a tablet-free interval of up to 7 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 first normal tablet-free interval, the possibility of a pregnancy should be considered.

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, a new (replacement) 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 tablet(s) from another blister pack.

How to postpone a withdrawal bleed

To delay a period the woman should continue with another blister pack of Elevin without a tablet-free interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of Elevin is then resumed after the usual 7-day tablet-free interval.

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

4.3 Contraindications

Combined oral contraceptives (COCs) should 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:

o diabetes mellitus with vascular symptoms o severe hypertension o 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)

•    Pancreatitis or a history thereof if associated with severe hypertriglyceridemia

•    Presence or history of severe hepatic disease as long as liver function values have not returned to normal

•    Presence or history of liver tumours (benign or malignant)

•    Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts)

•    Undiagnosed vaginal bleeding

•    History of migraine with focal neurological symptoms

•    Hypersensitivity to the active substances or to any of the excipients of Elevin film-coated tablets

4.4 Special warnings and precautions for use

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 woman 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 COC use should be discontinued.

Circulatory Disorders

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.

Epidemiological studies have shown that the incidence of VTE in women with no known risk factors for VTE who use low dose oestrogen (<50 pg ethinylestradiol combined oral contraceptives) ranges from about 20 cases per 100,000 woman-years (for levonorgestrel-containing COCs ) to 40 cases per 100,000 women-years (for desogestrel/ gestodene-containing COC). This compares with 5 to 10 cases per 100,000 woman-years for non-users and 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.

Epidemiological studies have also associated the use of combined COCs with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism.

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral 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

•    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.

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

•    increasing age

•    a positive family history (venous thromboembolism ever in a sibling or parent at relatively 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 thrombo-embolic 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)

•    dyslipoproteinemia

•    hypertension

•    migraine

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

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

•    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 (for information on "Pregnancy and Lactation" see section 4.6).

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) and sickle cell disease.

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 (> 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 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 preexisting 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 Elevin 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). 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 active tablets (see section 4.2), gastro-intestinal disturbances (see section 4.2) or concomitant medication (see section 4.5).

Reduced cycle control

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

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

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

Precautions for use

This medicinal product contains lactose monohydrate. Patients with the rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product (see section 2)

4.5 Interaction with other medicinal products and other forms of interaction

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

Influence of other medicinal products on Elevin

Interactions between oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature.

Hepatic metabolism

Interactions can occur with drugs that induce hepatic enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, bosentan and HIV-medication (e.g. ritonavir, nevirapine) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing the herbal remedy St. John's Wort (hypericum perforatum)). Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation of drug therapy.

Interference with Enterohepatic Circulation

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

Management

Women on short-term treatment with any of the above-mentioned classes of medicinal products or individual active substances (hepatic enzyme-inducing medicine) besides rifampicin should temporarily use a barrier method in addition to the COC, i.e. during the time of concomitant medicinal product administration and for 7 days after their discontinuation.

For women on rifampicin a barrier method should be used in addition to the COC during the time of rifampicin administration and for 28 days after its discontinuation.

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.

Women on treatment with antibiotics (besides rifampicin, see above) should use the barrier method until 7 days after discontinuation.

If concomitant medicinal product administration runs beyond the end of the tablets in the COC blister pack, the next COC pack should be started without the usual tablet-free interval.

Influence of Elevin on other medicinal products

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

Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone at doses of 3 mg with the metabolism of other active substances is unlikely.

Laboratory tests

The use of contraceptive steroids 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. Changes generally remain within the normal laboratory range.

4.6 Pregnancy and lactation

Elevin is not indicated during pregnancy.

If pregnancy occurs during use of Elevin, the preparation should be withdrawn immediately. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during pregnancy.

Animal studies have shown undesirable effects during pregnancy and lactation (see section 5.3). Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with COCs during pregnancy did not provide evidence for an actual undesirable effect in humans.

The available data regarding the use of Elevin during pregnancy are too limited to permit conclusions concerning negative effects of Elevin on pregnancy, health of the foetus or neonate. To date, no relevant epidemiological data are available.

Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should generally not be recommended until the breast-feeding mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk during COC use. These amounts may affect the child.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of COCs.

4.8 Undesirable effects

For serious undesirable effects in COC users see section 4.4.

The following adverse drug reactions have been reported during use of Elevin:

The frequency classes are defined as follows:

Very common:    > 1/10

> 1/100 to < 1/10

The very common undesirable effects (>10%) in connection with taking Elevin are headaches (including migraine) and spotting and intracyclic menstrual bleeding. The following undesirable effects were observed taking combined oral contraceptives containing ethinylestradiol/ levonorgestrel:

organ system	frequency of undesirable effects
	common	uncommon	rare	very rare	unknown
Infections and infestations	vaginitis, including candidiasis
Immune system disorders			allergic reactions	urticaria, angiooedema, anaphylactic reaction	worsening of systemic lupus ery- thematodes, herpes gestationis
Metabolism and nutrition disorders		changes in appetite (increase or decrease)	glucose intolerance
Psychiatric disorders	mood shifts, including depression; changes in libido
Nervous system disorders	nervousness and dizziness				worsening of chorea minor (Sydenham)
Eye disorders			incompatibility with contact lenses		optic nerve inflammation (may cause partial or complete loss of vision)
Gastro intestinal disorders	nausea, vomiting, abdominal pain	abdominal cramps and bloating			ischemic colitis, worsening of chronic- inflammatory intestinal diseases (Crohn’s disease and ulcerative colitis)
Hepato-biliary disorders			cholestatic jaundice		pancreatitis with simultaneous

					serious hypertriglycer idaemia, gall bladder disease including gall stones (combined oral contraceptive can cause the occurrence of gall bladder disease or exacerbate a previously existing gall bladder disease)
Skin and subcutaneous tissue disorders	acne	rash, chloasma, hirsutism, alopecia	erythema nodosum	erythema multiforme
Reproductive system and breast disorders	breast pain, sensitivity of the breasts, breast enlargement, mammary gland secretion, dysmenorrhoea, changes in the menstruation flow, changes on the cervix and in cervical secretion, amenorrhoea
General disorders and administration site conditions	fluid retention				worsening of varicosis, haemolytic- uremic syndrome, otosclerosisw orsening of porphyria
Investigations	changes in weight (increase or decrease)	increased blood pressure, changes in the blood lipid levels,

		including hyper- triglyceri- daemia
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)				hepatocellular carcinoma, benign liver tumors (e.g. focal nodular hyperplasia, hepatic adenoma)

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

•    Venous thromboembolic disorders

•    Arterial thromboembolic disorders

•    Hypertension

•    Liver tumours

•    Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, migraine, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice

•    Chloasma

•    Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal

•    In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema

The frequency of diagnosis of breast cancer is very slightly increased among OC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and 4.4.

4.9 Overdose

There has not yet been any experience of overdose with Elevin. On the basis of general experience with combined oral contraceptives, symptoms that may possibly occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding.. There are no antidotes and treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations

ATC-Code: G03AA07

Elevin tablet is a combined oral contraceptive and contains ethinylestradiol (EE) and levonorgestrel.

Ethinylestradiol

Ethinylestradiol is an oral synthetic oestrogen. Similar to the natural estradiol, ethinylestradiol has a proliferative effect on the epithelia of the female genital organs. It stimulates the production of the cervical mucus and reduces its viscosity. Ethinylestradiol promotes the growth of the ductus lactiferi and inhibits lactation. Ethinylestradiol also increased extracellular retention of fluid and affects lipid and carbohydrate metabolism, haemostsis, the renin-angiotensin-aldosteron system and the serum binding proteins.

Levonorgestrel

Levonorgestrel has progestogenic effects on the secretory conversion of the endometrium. Levonorgestrel brakes gonadotropin secretion in the front lobes of the pituitary gland. In addition, levonorgestrel has anti-oestrogenic and low androgenic effects.

5.2 Pharmacokinetic properties

Levonorgestrel

Absorption

Levonorgestrel is absorbed quickly and completely after oral administration and the maximum levonorgestrel serum concentrations of approximately 4-6 ng/ml are reached approximately 2 hours after taking it. Bioavailability is almost 90%.

Distribution

Levonorgestrel is linked to serum albumin and sexual hormone bonding globulin (SHBG). Only 1.1% of the total concentration of the medicinal product in the serum is a free steroid, approximately 65% is specifically linked to SHBG and approximately 35% is non-specifically linked to albumin. The increase in SHBG induced by ethinylestradiol influences the relative distribution of levonorgestrel in various protein fractions. Inducing the bonding protein causes an increase in the SHBG-bound fraction and a decrease of the albumin-bound fraction. The apparent volume of distribution of levonorgestrel is 129 l after one dosage.

Metabolism

Levonorgestrel is metabolised primarily by reduction on the A4-3-oxo-group and hydroxylation on positions 2a, 1P and 16P and then conjugation. The majority of metabolites circulating in the blood are sulphates of the 3a,    5P-

tetrahydrolevonorgestrel, while it is primarily excreted in the form of glucuronides. A part of the unchanged levonorgestrel also circulates as 17P-sulphate. The metabolic clearance may vary interindividually by multiples and this might explain some of the great fluctuations observed in the levonorgestrel concentrations among users.

Elimination

The serum levels of levonorgestrel drop two phases. The terminal phase is marked by a half-life of approximately 25 hours. Levonorgestrel and its metabolites are mostly eliminated with the urine (40%-68%) and approximately 16%-48% with the faeces.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of about 33 pg/ml are reached within 1 - 2 hours after single oral administration. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60 %. Concomitant intake of food reduced the bioavailability of ethinylestradiol in about 25 % of the investigated subjects while no change was observed in the others.

Distribution

Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5 %), and induces an increase in the serum concentrations of SHBG and corticoid binding globulin (CBG). An apparent volume of distribution of about 5 l/kg was determined.

Metabolism

Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate of ethinylestradiol is about 5 ml/min/kg.

Elimination

Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Steady-state conditions are reached during the second half of a treatment cycle and serum levels of ethinylestradiol accumulate by a factor of about 2.0 to 2.3.

5.3 Preclinical safety data

The toxicity profile of ethinylestradiol and levonorgestrel is well known. The findings of animal experiments with oestrogens only have limited predicative value for using it on humans due to pronounced species differences. Ethinylestradiol showed an embryolethal effect in experimental animals at a relatively low dosage; malformations of the urogenital tract and feminisations of male foetuses have been observed; levonorgestrel showed an embryolethal effect in animal experiments and virilising effect on female foetuses at high dosages. Reproduction toxicological studies in rats, mice and rabbits did not bring about any indication a teratogenic effect. Preclinical data for ethinylestradiol and levonorgestrel from conventional studies on chronic toxicity, genotoxicity and carcinogenic potential do not indicate any relevant risks for humans with the exception of those already described in the other sections of the summary of product characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

lactose monohydrate maize starch gelatin

magnesium stearate

Tablet coating: hypromellose (3 cps)

Macrogol 4000

titanium dioxide (E171) iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC/PVDC aluminium blister packs or PP/COC/PP aluminium packs with 21 film-coated tablets (calendar packs).

Pack sizes:

21 film-coated tablets

3 x 21 film-coated tablets

6 x 21 film-coated tablets

13 x 21 film-coated tablets

100 x 21 film-coated tablets (hospital pack)

Not all pack sizes may be marketed.

Special precautions for disposal

No special requirements.

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

7. MARKETING AUTHORISATION HOLDER

9, St George’s Yard Castle Street Farnham Surrey GU9 7LW

8    MARKETING AUTHORISATION NUMBER(S)

PL 36876/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 10/03/2010

10 DATE OF REVISION OF THE TEXT

16/05/2016