Organon Laboratories Limited

Marviol 150/30 microgram Tablets.

Each tablet contains desogestrel 150 microgram and ethinylestradiol 30 microgram

Also contains approximately 68mg Lactose Monohydrate

For a full list of excipients see section 6.1.

Tablet

The tablets are white, round, biconvex, and 6mm in diameter. They are coded on one side 'Organon' and an asterix '*' and on the reverse side 'TR' above '5'..

Contraception.

Before starting Marviol, a thorough general medical and gynaecological examination(including breasts and a cytological smear of the cervix, if appropriate) should be carried out and the family medical history carefully noted. Disturbances of the clotting mechanisms should be ruled out if any members of the family have suffered from thromboembolic diseases (e.g. deep vein thrombosis, stroke, myocardial infarction) at a young age.

Pregnancy must be excluded ideally by a pregnancy test.

As a precaution, thorough examinations should be conducted at approximately six month intervals during the use of the tablets.

How to take Marviol

Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. 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 taking Marviol

No preceding hormonal contraceptive

Tablet taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). Starting on day 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 Marviol preferably on the day after the last active tablet (the last tablet containing the active substance) 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 a transdermal patch has been used, the woman should start using Marviol preferably on the day of removal, but at the latest when the next application would have been due. Not all contraceptive methods (transdermal patch, vaginal ring) may be marketed in all EU countries.

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 miscarriage

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

Following delivery or second-trimester miscarriage

For breastfeeding women see Section 4.6.

Women should be advised to start at day 21 to 28 after delivery or second trimester miscarriage. 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

If the user is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the 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 pill 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 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 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. 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 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 the tablets at her usual time. The next pack must be started as soon as the current 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 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 pack.

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

Advice on gastro-intestinal disturbances

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

If vomiting occurs within 3-4 hours after tablet-taking, the advice concerning missed tablets, as given in Section 4.2.3, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.

How to shift periods or how to delay a period

Delaying a period is not an indication for the product. However, if in exceptional cases a period needs to be delayed the woman should continue with another pack of Marviol 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 Marviol is then resumed after the usual 7-day tablet-free interval.

To shift her period 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 second pack (just as when delaying a period).

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

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

• Presence or a history of venous thrombosis (deep venous thrombosis, pulmonary embolism)

• Presence or history of arterial thrombosis (myocardial infarction, cerebrovascular accident) or prodromal conditions (e.g. transient ischaemic attack, angina pectoris)

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

• Recent severe of history of recurrent migraine both with focal neurological symptoms (see section 4.4).

• Diabetes mellitus with vascular involvement

• Severe hypertension

• Severe dyslipoproteinemia

• Known predisposition for venous or arterial thrombosis, such as Activated Protein C (APC) resistance, antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, and antiphospholipid antibodies.

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

• Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia.

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

• Undiagnosed vaginal bleeding.

• Endometrial hyperplasia.

• Hypersensitivity to any of the active substances of Marvelon or to any of the excipients.

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.

Conditions which need supervision

− Risk factors for thrombo-embolic disorders (see below)

− Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer

− Hypertension

− Liver disorders (e.g. liver adenoma)

− Cholelithiasis, jaundice and/or pruritus related to cholestasis

− Herpes gestationis

− Migraine or (severe) headache

− Systemic lupus erythematosus

− Endogenous depression

− Asthma

− Otosclerosis-related hearing loss

− Porphyria

1. Circulatory Disorders

• The use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use. The incidence of VTE is considered to be 5-10 per 100,000 woman years in non-COC users. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. The risk of VTE associated with pregnancy is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.

• In several epidemiological studies it has been found that women using combined oral contraceptives with ethinylestradiol, mostly with a dose of 30 µg, and a progestin such as desogestrel have an increased risk of VTE compared with those using combined oral contraceptives containing less than 50 µg of ethinylestradiol and the progestin levonorgestrel.

• For brands containing 30 µg ethinylestradiol combined with desogestrel or gestodene compared with those containing less than 50 µg ethinylestradiol and levonorgestrel, the overall relative risk of VTE has been estimated to range between 1.5 and 2.0. The incidence of VTE for levonorgestrel containing combined oral contraceptives with less than 50 µg of ethinylestradiol is approximately 20 cases per 100,000 women-years of use. For Marviol tablets the incidence is approximately 30-40 per 100,000 women-years of use: i.e. additional 10-20 cases per 100,000 women-years of use. The impact of the relative risk on the number of additional cases would be greatest in women during the first year they ever use a combined oral contraceptive when the risk for VTE with all combined oral contraceptives is highest.

• The risk of venous thromboembolism increases with:

- increasing age;

- a positive family history (i.e. venous thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use;

- prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization;

- obesity (body mass index over 30 kg/m²);

- and possibly also with superficial thrombophlebitis and varicose veins. There is no consensus about the role of these conditions in the etiology of venous thromboembolism;

• the increased risk of venous thromboembolism in the puerperium must be considered (for information on “Pregnancy and Lactation” see Section 4.6).

• The use of COCs in general has been associated with an increased risk of acute myocardiol infarction (AMI) or stroke, a risk that is strongly influenced by the presence of other risk factors (e.g. smoking, high blood pressure, and age) (see also below). These events occur rarely. It has not been studied how Marviol modifies the risk of AMI.

• The risk of arterial thrombotic/thromboembolic events increases with:

- increasing age;

- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);

- dyslipoproteinemia;

- obesity (body mass index over 30 kg/m²);

- hypertension;

- migraine;

- valvular heart disease;

- atrial fibrillation;

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

• Extremely rarely thrombosis has been reported to occur in other blood vessels e.g. hepatic, meserteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

• Symptoms of venous or arterial thrombosis can include: 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. Occurrence of one or more of these symptoms may be a reason for immediate discontinuation of Marvelon usage.

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

• The increased risk of thromboembolism in the puerperium must be considered (for information on “Pregnancy and Lactation” see Section 4.6).

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

• 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.

All this information should be taken into account when prescribing this oral contraceptive. When counselling on the choice of contraceptive method(s), all the above information should be considered.

2 Tumours

• Some epidemiological studies indicate that the long-term use of oral contraceptives displays a risk factor for the development of cervical cancer in women infected with human papillomavirus (HPV). Howver, there is still controversy about the extent to which this finding is influenced by to confounding effects (e.g.differences in number of sexual partners or in use of barrier contraceptives).

• 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 haemorrhage. 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.

3. 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. A relationship between COC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.

• The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritis related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.

• Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

• Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COC (containing <0.05mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.

• 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.

• Marviol contains <80mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on lactose-free diet should take this amount into consideration.

When counselling the choice of contraceptive method(s), all the above information should be taken into account.

Medical Examination/Consultation

Prior to the initiation or reinitiation of Gracial, a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and if clinically indicated a physical examination should be performed, guided by the contraindications (section 4.3) and warnings (section 4.4.). The woman should also be instructed to carefully read the user leaflet and adhere to the advice given. The frequency and nature of further periodic checks 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 (section 4.2), gastro-intestinal disturbances (section 4.2) or concomitant medication (section 4.5).

Herbal preparations containing St. John's wort (Hypericum perforatum) should not be used while taking Marvelon due to the risk of decreased plasma concentrations and reduced clinical effects of Marvelon (see Section 4.5 Interactions)

Reduced cycle control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first three months of use.

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

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.

Interactions

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

Hepatic metabolism: Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones (e.g. hydantoins, barbiturates, primidone, hydantoins, phenylbutazone, rifampicin, carbamazepine and possibly also oxcarbazepine topiramate, felbamate, ritonavir, griseofulvin and products containing St. John's wort. Maximal enzyme induction is generally not seen for 2 – 3 weeks, but may then be sustained for at least 4 weeks after the cessation of drug therapy.

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

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, the barrier method should be used during the time of concomitant drug administration and for 28 days after discontinuation. In case of long-term treatment with microsomal enzyme-inducing drugs another method of contraception should be considered. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the tablets in the COC pack, the next COC pack should be started without the usual tablet-free period.

In women on long-term treatment with microsomal enzyme-inducing drugs, experts have recommended to increase the contraceptive steroid doses. If a high contraceptive dosage is not desirable or appears to be unsatisfactory or unreliable, e.g. in the case of irregular bleeding, another, nonhormonal, method of contraception should be advised.

Herbal preparations containing St John's wort should not be taken concomitantly with oral contraceptives.

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

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

Mercilon is not indicated during pregnancy.

If pregnancy occurs during treatment with Marviol, further intake should 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 during pregnancy.

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 but there is no evidence that this adversely affects infant health.

No observed effects.

Possibly related undesirable effects that have been reported in users of Marviol or COC users in general are listed in the table below¹:

¹ The most common appropriate MedDRA term (version 9.0) to describe a certain adverse event reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

A number of undesirable effects have been reported in women using combined oral contraceptives, which are discussed in more detail in Section 4.4 Special Warnings and Precautions for Use. These include: venous thromboembolic disorders; arterial thromboembolic disorders; hypertension; hormone-dependent tumours (e.g. liver tumours, breast cancer); chloasma.

There have been no reports of serious deleterious 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.

ATC classification G03A A09.

The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion. As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warnings, Undesirable effects), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. In the largest multicenter trial (n=23 258 cycles), the uncorrected Pearl Index is estimated at 0.1 (95% confidence interval 0.0-0.3). Furthermore, 4.5% of the women reported absence of withdrawal bleeding and 9.2% reported occurrence of irregular bleeding after 6 treatment cycles.

Apart from this, with the higher-dosed COCs (50 μg ethinylestradiol), there is evidence of a reduced risk of fibrocystic tumours of the breasts, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy and endometrial and ovarian cancer. Whether this also applies to lower-dosed COCs remains to be confirmed.

Desogestrel

ABSORPTION

Orally administered desogestrel is rapidly and completely absorbed and converted to etonogestrel. Peak serum concentrations are reached at about 1.5 hours after single ingestion. Bioavailability is 62-81 %.

DISTRIBUTION

Etonogestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 2-4% of the total serum drug concentrations are present as free steroid, 40-70% are specifically bound to SHBG. The ethinylestradiol-induced increase in SHBG influences the distribution over 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 desogestrel is 1.5 l/kg.

METABOLISM

Etonogestrel is completely metabolised by the known pathways of steroid metabolism. The metabolic clearance rate from serum is about 2 ml/min/kg. No interaction was found with the co-administered ethinylestradiol.

ELIMINATION

Etonogestrel serum levels decrease in two phases. The terminal disposition phase is characterised by a half-life of approximately 30 hours. Desogestrel and its metabolites are extracted at a urinary to biliary ratio of about 6:4.

STEADY-STATE CONDITIONS

Etonogestrel pharmacokinetics is influenced by SHBG levels, which are increased threefold by ethinylestradiol. Following daily ingestion, drug serum levels increase about two- to threefold, reaching steady state conditions during the second half of the treatment cycle.

Ethinylestradiol

ABSORPTION

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations are reached within 1-2 hours. Absolute bioavailability as a result of pre-synaptic coagulation and first pass metabolism is approximately 60%

DISTRIBUTION

Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 5 l/kg was determined.

METABOLISM

Ethinylestradiol is subject to presynaptic 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 glucronides and sulphate. The metabolic clearance rate is about 5 ml/min/kg.

ELIMINATION

Ethinylestradiol serum levels decrease in two disposition phases, the terminal disposition phase is characterised by a half-life of approximately 24 hours. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

STEADY-STATE CONDITIONS

Steady state concentrations are reached after 3-4 days when serum drug levels are higher by 30-40% compared to single dose.

Preclinical data reveal no special risk for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

All-rac-α-tocopherol

Potato Starch

Povidone

Stearic acid

Silica, colloidal anhydrous

Lactose monohydrate

Not applicable

3 years

Store below 25^oC. Store in the original package in order to protect from light.

PVC/aluminium blister, which is packed in an aluminium laminated sachet.

Pack sizes: 3 x 21 tablets.

Each blister contains 21 tablets.

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

Organon (Ireland) Ltd

P O Box 2857

Drynam Road

Swords

Co Dublin

PA61/16/1

13 April 1983 / 13 April 2008

Jan 2010