Femodene ^®

Each tablet contains:

Actives:

Gestodene 75 micrograms

Ethinylestradiol 30 micrograms

Excipients:

Lactose 37.43 mg

Sucrose 19.66 mg

For full list of excipients, see section 6.1

Sugar-coated tablets

Oral contraception and the recognised gynaecological indications for such oestrogen-progestogen combinations.

First treatment cycle: 1 tablet daily for 21 days, starting on the first day of the menstrual cycle. Contraceptive protection begins immediately.

Subsequent cycles: Tablet taking from the next pack of Femodene is continued after a 7-day interval, beginning on the same day of the week as the first pack.

Changing from 21-day combined oral contraceptives: The first tablet of Femodene should be taken on the first day immediately after the end of the previous oral contraceptive course. Additional contraceptive precautions are not required.

Changing from a combined Every Day pill (28 day tablets):

Femodene should be started after taking the last active tablet from the Every Day Pill pack. The first Femodene tablet is taken the next day. Additional contraceptive precautions are not then required.

Changing from a progestogen-only pill (POP):

The first tablet of Femodene should be taken on the first day of bleeding, even if a POP has already been taken on that day. Additional contraceptive precautions are not then required. The remaining progestogen-only pills should be discarded.

Post-partum and post-abortum use: After pregnancy, oral contraception can be started 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first 7 days of tablet taking. Since the first post-partum ovulation may precede the first bleeding, another method of contraception should be used in the interval between childbirth and the first course of tablets. After a first-trimester abortion, oral contraception may be started immediately in which case no additional contraceptive precautions are required.

Special circumstances requiring additional contraception

Incorrect administration: A single delayed tablet should be taken as soon as possible, and if this can be done within 12 hours of the correct time, contraceptive protection is maintained. With longer delays, additional contraception is needed. Only the most recently delayed tablet should be taken, earlier missed tablets being omitted, and additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used for the next 7 days, while the next 7 tablets are being taken. Additionally, therefore, if tablet(s) have been missed during the last 7 days of a pack, there should be no break before the next pack is started. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on tablet taking days but this is not clinically significant. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack.

Gastro-intestinal upset: Vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. Tablet-taking from the current pack should be continued. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used during the gastro-intestinal upset and for 7 days following the upset. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack. Other methods of contraception should be considered if the gastro-intestinal disorder is likely to be prolonged.

1. Pregnancy

2. Severe disturbances of liver function, jaundice or persistent itching during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, previous or existing liver tumours.

3. History of confirmed venous thromboembolism (VTE). Family history of idiopathic VTE. Other known risk factors for VTE.

4. Existing or previous arterial thrombotic or embolic processes, conditions which predispose to them e.g. disorders of the clotting processes, valvular heart disease and atrial fibrillation.

5. Sickle-cell anaemia.

6. Mammary or endometrial carcinoma, or a history of these conditions.

7. Severe diabetes mellitus with vascular changes.

8. Disorders of lipid metabolism.

9. History of herpes gestationis.

10. Deterioration of otosclerosis during pregnancy.

11. Undiagnosed abnormal vaginal bleeding.

12. Hypersensitivity to any of the components of Femodene.

Warnings: Some epidemiological studies have suggested an association between the use of combined oral contraceptives (COCs) and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism. These events occur rarely. Full recovery from such disorders does not always occur, and it should be realised that in a few cases they are fatal.

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. Some epidemiological studies have reported a greater risk of VTE for women using combined oral contraceptives containing desogestrel or gestodene (the so-called third generation pills) than for women using pills containing levonorgestrel (the so-called second generation pills).

The spontaneous incidence of VTE in healthy non-pregnant women (not taking any oral contraceptive) is about 5 cases per 100,000 women per year. The incidence in users of second generation pills is about 15 per 100,000 women per year of use. The incidence in users of third generation pills is about 25 cases per 100,000 women per year of use; this excess incidence has not been satisfactorily explained by bias or confounding. The level of all of these risks of VTE increases with age and is likely to be further increased in women with other known risk factors for VTE such as obesity.

The risk of venous and/or arterial thrombosis associated with combined oral contraceptives increases with:

• age;

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

• a positive family history (i.e. venous or arterial 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 COC use;

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

• dyslipoproteinaemia;

• hypertension;

• valvular heart disease;

• atrial fibrillation;

• prolonged immobilisation, 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 six weeks in advance) and not to resume until two weeks after complete remobilisation.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

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 circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), sickle cell disease and subarachnoid haemorrhage.

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, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COC use.

Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer.

An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors.

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 combined oral contraceptives (COCs). 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 additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.

Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with 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 (see bar chart).

The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.

The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

Estimated cumulative numbers of breast cancers per 10,000 women diagnosed in 5 years of use and up to 10 years after stopping COCs, compared with numbers of breast cancers diagnosed in 10,000 women who had never used COCs

The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of combined oral contraceptives (see 'Precautions').

The combination of ethinylestradiol and gestodene, like other contraceptive steroids, is associated with an increased incidence of neoplastic nodules in the rat liver, the relevance of which to man is unknown. Malignant liver tumours have been reported on rare occasions in long-term users of oral contraceptives.

In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Femodene. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumour should be included in the differential diagnosis.

Reasons for stopping oral contraception immediately:

1. Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches.

2. Sudden disturbances of vision, of hearing or other perceptual disorders.

3. First signs of thrombophlebitis or thromboembolic symptoms (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest.

4. Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin.

5. Onset of jaundice, hepatitis, itching of the whole body.

6. Increase in epileptic seizures.

7. Significant rise in blood pressure

8. Onset of severe depression.

9. Severe upper abdominal pain or liver enlargement.

10. Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy.

11. Pregnancy is a reason for stopping immediately because it has been suggested by some investigations that oral contraceptives taken in early pregnancy may slightly increase the risk of foetal malformations. Other investigations have failed to support these findings. The possibility therefore cannot be excluded, but it is certain that if a risk exists at all, it is very small.

Precautions:

Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.

The following conditions require strict medical supervision during medication with oral contraceptives. Deterioration or first appearance of any of these conditions may indicate that use of the oral contraceptive should be discontinued:

Diabetes mellitus, or a tendency towards diabetes mellitus (e.g. unexplained glycosuria) hypertension, varicose veins, a history of phlebitis, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, disturbed liver function, Sydenham's chorea, renal dysfunction, family history of clotting disorders (see also contraindications) obesity, family history of breast cancer and patient history of benign breast disease, history of clinical depression, systemic lupus erythematosus, uterine fibroids, an intolerance of contact lenses, migraine, gall-stones, cardiovascular diseases, chloasma, asthma, or any disease that is prone to worsen during pregnancy.

Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of oral contraceptives, especially when these conditions existed prior to use. Women should be informed of this possibility.

Hepatic enzyme inducers such as barbiturates, primidone, phenobarbitone, phenytoin, phenylbutazone, rifampicin, carbamazepine and griseofulvin can impair the efficacy of Femodene. For women receiving long-term therapy with hepatic enzyme inducers, another method of contraception should be used. The use of antibiotics may also reduce the efficacy of Femodene, possibly by altering the intestinal flora.

Women receiving short courses of enzyme inducers or broad spectrum antibiotics should take additional, non-hormonal (except rhythm or temperature method) contraceptive precautions during the time of concurrent medication and for 7 days afterwards. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack. With rifampicin, additional contraceptive precautions should be continued for 4 weeks after treatment stops, even if only a short course was administered.

The requirement for oral antidiabetics or insulin can change as a result of the effect on glucose tolerance.

The herbal remedy St John's wort (Hypericum perforatum) should not be taken concomitantly with Femodene as this could potentially lead to a loss of contraceptive effect.

If pregnancy occurs during medication with oral contraceptives, the preparation should be withdrawn immediately (see Section 4.4. 'Reasons for stopping oral contraception immediately').

The use of Femodene during lactation may lead to a reduction in the volume of milk produced and to a change in its composition. Minute amounts of the active substances are excreted with the milk. Mothers who are breast-feeding may be advised instead to use a progestogen-only pill.

None known.

In rare cases, headaches, gastric upsets, nausea, vomiting, breast tenderness, changes in body weight, changes in libido, depressive moods can occur.

In predisposed women, use of Femodene can sometimes cause chloasma which is exacerbated by exposure to sunlight. Such women should avoid prolonged exposure to sunlight.

Individual cases of poor tolerance of contact lenses have been reported with use of oral contraceptives. Contact lens wearers who develop changes in lens tolerance should be assessed by an ophthalmologist.

Menstrual changes:

1. Reduction of menstrual flow: This is not abnormal and it is to be expected in some patients. Indeed, it may be beneficial where heavy periods were previously experienced.

2. Missed menstruation: Occasionally, withdrawal bleeding may not occur at all. If the tablets have been taken correctly, pregnancy is very unlikely. If withdrawal bleeding fails to occur at the end of a second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.

Intermenstrual bleeding: 'Spotting' or heavier 'breakthrough bleeding' sometimes occur during tablet taking, especially in the first few cycles, and normally cease spontaneously. Femodene should therefore, be continued even if irregular bleeding occurs. If irregular bleeding is persistent, appropriate diagnostic measures to exclude an organic cause are indicated and may include curettage. This also applies in the case of spotting which occurs at irregular intervals in several consecutive cycles or which occurs for the first time after long use of Femodene.

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

Refer to Section 4.4. 'Special warnings and precautions for use' for additional information.

Overdosage may cause nausea, vomiting and, in females, withdrawal bleeding.

There are no specific antidotes and treatment should be symptomatic.

This oestrogen-progestogen combination acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinising hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.

Gestodene

Orally administered gestodene is rapidly and completely absorbed. Following single ingestion of Femodene, maximum drug serum levels of 4ng/ml are reached at about 1.0 hour. Thereafter, gestodene serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of 12 - 15 hours. For gestodene, an apparent volume of distribution of 0.7 l/kg and a metabolic clearance rate from serum of about 0.8 ml/min/kg were determined. Gestodene is not excreted in unchanged form but as metabolites, which are eliminated with a half-life of about 1 day. Gestodene metabolites are excreted at a urinary to biliary ratio of about 6:4. The biotransformation follows the known pathways of steroid metabolism. No pharmacologically active metabolites are known.

Gestodene is bound to serum albumin and to SHBG (sex hormone binding globulin). Only 1 - 2% of the total serum drug levels are present as free steroid, about 50 - 70% are specifically bound to SHBG. The relative distribution (free, albumin-bound, SHBG-bound) depends on the SHBG concentrations in the serum. Following induction of the binding protein, the SHBG-bound fraction increases while the unbound and the albumin-bound fractions decrease.

Following daily repeated administration of Femodene, gestodene concentrations in the serum increase by a factor of 2.8. Mean serum levels are fourfold higher at steady-state conditions which are reached during the second half of a treatment cycle. The pharmacokinetics of gestodene is influenced by SHBG serum levels. Under treatment with Femodene, a threefold increase in the serum SHBG levels has been observed for the first treatment cycle. Due to the specific binding of gestodene to SHBG, the increase in SHBG levels is accompanied by an almost parallel increase in gestodene serum levels. After three treatment cycles the extent of SHBG induction per cycle does not change any more. The absolute bioavailability of gestodene was determined to be 99% of the dose administered.

Ethinylestradiol

Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of Femodene, maximum drug serum levels of 82pg/ml are reached at 1.4 hours. Thereafter, ethinylestradiol serum levels decrease in two phases characterized by half-lives of 1 - 2 hours and about 20 hours. Because of analytical reasons, these parameters can only be calculated following the administration of higher doses. For ethinylestradiol, an apparent volume of distribution of about 5 l/kg and a metabolic clearance rate from serum of about 5ml/min/kg were determined. Ethinylestradiol is highly but non-specifically bound to serum albumin. About 2% of drug levels are present unbound. During absorption and first liver passage, ethinylestradiol is metabolized resulting in a reduced absolute and variable oral bioavailability. Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.

According to the half-life of the terminal disposition phase from serum and the daily ingestion, steady-state serum levels are reached after 3 - 4 days and are higher by 30 - 40% as compared to a single dose.

During established lactation, 0.02% of the daily maternal dose could be transferred to the newborn via milk.

The systemic availability of ethinylestradiol might be influenced in both directions by other drugs. There is, however, no interaction with high doses of vitamin C. Ethinylestradiol induces the hepatic synthesis of SHBG and CBG (corticoid binding globulin) during continuous use. The extent of SHBG induction, however, depends on the chemical structure and the dose of the co-administered progestogen. During treatment with Femodene, SHBG concentrations in the serum increased from 69nmol/l to 198nmol/l in the first and to 210nmol/l in the third cycle. Serum concentrations of CBG were increased from 37μg/ml to 85μg/ml in the first cycle and remained constant thereafter.

There are no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

lactose

maize starch

povidone

magnesium stearate (E 572)

sodium calcium edetate

sucrose

macrogol 6000

calcium carbonate (E 170)

talc

montan glycol wax

None known.

5 years.

Not applicable.

Deep drawn strips made of polyvinyl chloride film with counter-sealing foil made of aluminium with heat sealable coating.

Presentation:

Carton containing memo-packs of either 1 x 21 tablets or 3 x 21 tablets.

No special requirements.

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

United Kingdom

Trading as Bayer plc, Bayer Schering Pharma

PL 00010/0529

1 May 2008

29 October 2009