SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Alegria 100 / 20 microgram film-coated tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pink film-coated tablet contains 100 micrograms Levonorgestrel and 20 micrograms Ethinylestradiol.

Excipients with known effect:

Each film-coated tablet contains 66.94 mg of lactose.

Alegria also contains white placebo film-coated tablets.

Excipients with known effect:

Each placebo film-coated tablet contains 67.06 mg of lactose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet Active:

Pink, cylindrical, biconvex, film coated tablet of 6 mm approximately.

Placebo:

White, cylindrical, biconvex, film coated tablet of 6 mm approximately.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Oral contraception.

4.2    Posology and method of administration

Posology

How to take Alegria

Tablets must be taken 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 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous pack. A withdrawal bleed usually occurs. This usually starts on day 2-3 after beginning with placebo tablets and may not have finished before the next pack is started.

How to start Alegria

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 during the first cycle a barrier method is recommended in addition for the first 7 days of tablet-taking.

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

The woman should start with Alegria preferably on the day after the last hormone-containing tablet of her previous COC, but at the latest on the day following the usual tablet-free or hormone-free tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Alegria 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, injection, implant) or from a progestogen-releasing intrauterine system (IUS)

The woman may switch 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 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 For breastfeeding women see section 4.6

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 of 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.

Management of missed tablets

The last seven tablets of the blister strip are placebo tablets. If the user forgets any placebo tablet the effect of Alegria will not be affected. In any case the user has to discard the placebo forgotten tablet so as not extend the placebo period.

Next recommendations are applicable if the user forgets a tablet containing active substances (the first 21^st 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 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 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 placebo interval, the higher the risk of a 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 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 this is not the case, or if she 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 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, the woman should be advised to follow the first of these two options and to use extra 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 tablets at her usual time until finishing all active tablets. She must discard the seven tablets of the fourth row (placebo tablets). The next pack must be started immediately. 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 pack. She should then have a placebo-taking interval the last seven tablets of the blister strip) of up to 7 days, including the days she missed tablets, and subsequently continue with the next pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the first normal placebo-taking interval, the possibility of a pregnancy should be considered.

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbance, absorption of the active ingredients may not be complete and additional contraceptive measures should be taken.

If vomiting or severe diarrhoea occurs within 3-4 hours after taking a tablet, the woman should apply the advice concerning missed tablets.

In case of persisting or recurrent gastrointestinal disturbances, additional contraceptive measures should be taken and the physician should be informed.

How to shift periods or how to delay a period

To delay a period the woman should continue with another pack of Alegria without a r placebo 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 breakthroughbleeding or spotting. Regular intake of Alegria is then resumed after the usual placebo 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 placebo-taking 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 second pack (just as when delaying a period).

Method of administration

Oral use

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.

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

•    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).

•    Presence or history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).

•    Cerebrovascular accident present or in history

•    The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see section 4.4).

•    History of migraine with focal neurological symptoms.

•    Diabetes mellitus with vascular involvement.

•    Severe hepatic disease, current or previous, 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.

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.

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 cases per 100,000 woman-years (for levonorgestrel containing COCs) to 40 cases per 100,000 women-years (for desogestrel/gestoden containing COCs). This compares with 5 to 10 cases per 100,000 women-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.

Occurrence of one or more of these symptoms may be a reason for immediate discontinuation of Alegria.

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, especially migraine with focal neurological symptoms

•    valvular heart disease

•    atrial fibrillation

•    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.

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).

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.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

Tumours

The most important risk factor for cervical cancer is persistent HPV infection.

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 behavior 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 liver 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 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. A systematic 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 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 uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss, depression.

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 markers of liver function return to normal. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus which previously 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 of a need to alter the therapeutic regimen in diabetics using low dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully monitored, particularly in the early stage of COC use.

Worsening 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 while taking COCs.

Medical examination/consultation

Prior to the initiation or reinstitution of Alegria 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 tablets, vomiting or diarrhea or concomitant medication 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 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 placebo-taking 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.

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

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicaments on Alegria

Interactions between COCs and other drugs may impair the contraceptive efficacy and/or lead to breakthrough bleeding and/or contraceptive failure.

Reduced absorption:

Drugs that increase gastrointestinal motility, e.g. Metoclopramid, may reduce hormone absorption.

Substances diminishing the efficacy of COCs (enzyme-inducers and antibiotics)

• Enzyme induction (increase of hepatic metabolism):

Interactions can occur with drugs that induce microsomal hepatic enzymes, result ing in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin).

Herbal preparation containing St. John's wort should not be taken concomitantly with Alegria tablets as this could potentially lead to a loss of contraceptive efficacy. Breakthrough bleedings and unintended pregnancies have been reported. The enzyme inducing effect may persist for 2 weeks after cessation of treatment with St. John's wort.

Also HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have been reported to potentially increase hepatic metabolism.

•    Antibiotics (interference with enterohepatic circulation):

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

Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with COCs.

Women on treatment with any of these drugs should temporarily use a barrier method or another method of contraception in addition to the COC. With liver enzyme inducing drugs, the barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use a barrier method during the use of the antibiotics and until 7 days after their discontinuation. If the drug therapy runs beyond the end of the tablets in the COC pack, the next COC pack should be started right after the previous one without the usual placebo-taking interval.

Effects of COCs on other medication

Oral contraceptives may interfere with the metabolism of certain other drugs. Increased plasma concentrations of cyclosporin have been reported with concomitant administration of OCs. COCs have been shown to induce metabolism of lamotrigine resulting in sub-therapeutic plasma concentrations of lamotrigine..

Other forms of interactions

•    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.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Alegria is not indicated during pregnancy. If pregnancy occurs during treatment with Alegria, 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 at unintentional intake of contraceptive pills early pregnancy.

Breast-feeding

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 nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk. 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

Side effects that have been reported in users of COCs but for which the association has been neither confirmed nor refuted are *:

System Organ Class	Common £^1/100 to <1/100)	Uncommon £>1/1,000 to <1/100)	Rare £:1/10,000 to <1/1,000)
Immune system disorders			Hypersensitivity
Metabolism and nutrition disorders		Fluid retention
Psychiatric disorders	Depressed mood Mood altered	Libido decreased	Libido increased
Nervous system disorders	Headache	Migraine
Eye disorders			Contact lens intolerance
Gastrointestinal disorders	Nausea, Abdominal pain	Vomiting, Diarrhoea
Skin and subcutaneous tissue disorders		Rash, Urticaria	Erythema nodosum, Erythema multiforme
Reproductive system and breast disorders	Breast pain, Breast tenderness	Breast hypertrophy	Vaginal discharge, Breast discharge
Investigations	Weight increased		Weight decreased

* The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed but should be taken into account as well.

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4:

•    Venous thromboembolic disorders

•    Arterial thromboembolic disorders

•    Cerebrovascular accidents

•    Hypertension

•    Hypertriglyceridemia

•    Changes in glucose tolerance or effect on peripheral insulin resistance

•    Liver tumours (benign and malignant)

•    Liver function disturbances

•    Chloasma

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

•    Occurrence or deterioration of conditions for which association with COC use is not conclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss, Crohn's disease, ulcerative colitis, cervical cancer.

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.

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

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, website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There have been no reports of serious effects from overdose. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group (ATC): Progestogens and estrogens, fixed combinations; ATC Code: G03AA07.

Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.

The contraceptive effect of COCs is based on the interaction of various factors. The most important of these factors are the inhibition of ovulation and changes in the cervical mucus.

Clinical trials have been performed in 2498 women aged 18 to 40 years. The overall Pearl Index calculated from these trials was 0.69 (95% confidence interval 0.30 -1.36) based on 15,026 treatment cycles

5.2 Pharmacokinetic properties

Levonorgestrel

Absorption

Orally administered levonorgestrel is rapidly and completely absorbed. Peak serum concentrations of 2.3 ng/ml are reached at about 1.3 hours after single ingestion. Levonorgestrel is almost completely bioavailable after oral administration.

Distribution

Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 1.1% of the total serum drug concentrations are present as free steroid, approximately 65% are specifically bound to SHBG and about 34% are nonspecifically bound to albumin. The ethinylestradiol-induced increase in SHBG influences the proportion of levonorgestrel bound to the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The apparent volume of distribution of levonorgestrel is 129l.

Metabolism

Levonorgestrel is completely metabolised by the known pathways of steroid metabolism. The clearance rate from serum is approximately 1.0 ml/min/kg.

Elimination

Levonorgestrel serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 25 hours. Levonorgestrel is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:1. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Following daily ingestion drug serum levels increase about threefold reaching steady-state conditions during the second half of a treatment cycle. Levonorgestrel pharmacokinetics are influenced by SHBG levels, which are increased 1.5 - 1.6 fold when co-administered with ethinylestradiol. At steady-state, clearance rate and volume of distribution are slightly reduced to 0.7 ml/min/kg and about 100 l, respectively.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 50 pg/ml are reached within 1 - 2 hours. During absorption and first-liver passage, ethinylestradiol is metabolised extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 2065%.

Distribution

Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8 - 8.6 l/kg was reported.

Metabolism

Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised 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 sulphate. The metabolic clearance rate was reported to be 2.3 - 7 ml/min/kg.

Elimination

Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10 - 20 hours, respectively. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Ethinylestradiol serum concentrations increase about two-fold after daily oral administration of levonorgestrel/ethinylestradiol. According to the variable half-life of the terminal disposition phase from serum and the daily ingestion, steady-state serum levels of ethinylestradiol will be reached after about one week.

5.3    Preclinical safety data

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

Active film-coated tablets:    Placebo film-coated tablets:

Tablet core:

Lactose monohydrate,

Lactose monohydrate,

Polacrilin potassium, Microcrystalline cellulose, Magnesium stearate.

Tablet coating:

Opadry II Pink, consisting of: Macrogol 3350,

Titanium dioxide (E171), Polyvinyl alcohol,

Talc (E553b),

Iron oxide red (E172),

Iron oxide yellow (E172).

Polacrilin potassium, Microcrystalline cellulose, Magnesium stearate.

Tablet coating:

Opadry II White, consisting of: Macrogol 3350,

Titanium dioxide (E171), Polyvinyl alcohol,

Talc (E553b).

6.2    Incompatibilities

Not applicable

6.3    Shelf life

18 months

6.4    Special precautions for storage

Do not store above 30°C.

6.5    Nature and contents of container

Alegria is packed in PVC/PVDC /Aluminium blister packs of 28 tablets consisting of 21 active and 7 placebo tablets per blister.

Alegria is available is the following pack sizes 28 and 84tablets.

Not all pack sizes may be marketed

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Cyndea Pharma, S.L.

Poligono Industrial Emiliano Revilla Sanz Av. de Agreda 31, 42110 Olvega (Soria),

Spain

8    MARKETING AUTHORISATION NUMBER(S)

PL 37355/0003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/03/2014

10 DATE OF REVISION OF THE TEXT

27/03/2014