Logynon^® ED

Calendar pack containing 6 light brown tablets, 5 white tablets and 10 ochre-coloured tablets containing the following ingredients.

Each Light Brown Tablet contains:

Each White Tablet contains:

Each Ochre Tablet contains:

Loygnon ED also contains 7 large white placebo tablets.

Each placebo tablet contains:

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 28 days, starting on the first day of the menstrual cycle. 21 (small) active tablets are taken followed by 7 (larger) placebo tablets. Contraceptive protection begins immediately.

Subsequent cycles: Tablet taking is continuous, which means that the next pack of Logynon ED follows immediately without a break. A withdrawal bleed usually occurs when the white placebo tablets are being taken.

Changing from 21-day combined oral contraceptives: The first tablet of Logynon ED 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 pill): Logynon ED should be started after taking the last active tablet from the previous Every Day pill pack. The first Logynon ED tablet is taken the next day. Additional contraceptive precautions are not then required.

Changing from a progestogen-only pill (POP):

The first tablet of Logynon ED 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, Logynon ED 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: Errors in taking the 7 inactive white placebo tablets (i.e. the larger white tablets in the last row) can be ignored. A single delayed active (small) 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 in taking active tablets, 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 active (small) tablets are being taken. Therefore, if the 7 days additional contraception will extend beyond the last active (small) tablet, the user should finish taking all the active tablets, discard the placebo tablets and start a new pack of Logynon ED the next day with an appropriate active (small) tablet. Thus, active tablet follows active tablet with no 7 day break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on pill taking days but this is not clinically significant. If the patient does not have a withdrawal bleed 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 extend beyond the last active (small) tablet the user should finish taking all the active tablets, discard the placebo tablets and start a new pack of Logynon ED the next day with an appropriate active (small) tablet. 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 at 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. Existing or a history of confirmed venous thromboembolism (VTE), family history of idiopathic VTE and other known risk factors for VTE.

4. Existing or previous arterial thrombotic or embolic processes.

5. Conditions which predispose to them e.g. disorders of the clotting processes, valvular heart disease and atrial fibrillation

6. Sickle-cell anaemia

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

8. Severe diabetes mellitus with vascular changes

9. Disorders of lipid metabolism

10. History of herpes gestationis

11. Deterioration of otosclerosis during pregnancy

12. Undiagnosed abnormal vaginal bleeding

13. Hypersensitivity to any of the components of Logynon ED.

Warnings:

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 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 these risks 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').

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 Logynon ED. 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 or hearing or other perceptual disorders

2. 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

6. 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 some 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 (chorea minor), renal dysfunction, family history of clotting disorders, obesity, family history of breast cancer and patient history of benign breast disease, history of clinical depression, systemic lupus erythematosus, uterine fibroids and migraine, gall-stones, cardiovascular diseases, chloasma, asthma, an intolerance of contact lenses, 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.

Lactose and Sucrose Intolerance

Each light brown tablet contains 33.07 mg lactose and 19.297 mg sucrose per tablet. Each white tablet contains 33.035 mg lactose and 19.66 mg sucrose per tablet. Each ochre tablet contains 32.995 mg lactose and 19.223 mg sucrose per tablet. Each placebo tablet contains 48.25 mg lactose and 33.98 mg sucrose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, fructose intolerance or glucose-galactose malabsorption or sucrase-isomaltase should not take this medicine.

Hepatic enzyme inducers such as barbiturates, primidone, phenobarbitone, phenytoin, phenylbutazone, rifampicin, carbamazepine and griseofulvin can impair the efficacy of Logynon ED. 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 Logynon ED, possibly by altering the intestinal flora.

Women receiving short courses of enzyme inducers or broad spectrum antibiotics should take additional, non-hormonal (except the rhythm or temperature methods) contraceptive precautions during the time of concurrent medication and for 7 days afterwards. If these 7 days extend beyond the last active (small) tablet the user should finish taking all the active tablets, discard the placebo (large) tablets and start a new pack of Logynon ED the next day with an appropriate active (small) tablet. 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 at 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 Logynon ED as this could potentially lead to a loss of contraceptive effect.

Logynon ED is not indicated during pregnancy. If pregnancy occurs during treatment with Logynon ED, further intake must be stopped. However, extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy.

The use of Logynon ED 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 another method of contraception.

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 Logynon ED 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. Logynon ED 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 Logynon ED.

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 special 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.

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

Levonorgestrel

Orally administered levonorgestrel is rapidly and completely absorbed. Following ingestion of 0.125mg levonorgestrel together with 0.03mg ethinylestradiol (which represents the combination with the highest levonorgestrel content of the tri-step formulation), maximum drug serum levels of about 4.3ng/ml are reached at 1.0 hour. Thereafter, levonorgestrel serum levels decrease in two phases, characterized by half-lives of 0.4 hours and about 22 hours. For levonorgestrel, a metabolic clearance rate from serum of about 1.5ml/min/kg was determined. Levonorgestrel is not excreted in unchanged form but as metabolites. Levonorgestrel metabolites are excreted in about equal proportions with urine and faeces. The biotransformation follows the known pathways of steroid metabolism. No pharmacologically active metabolites are known.

Levonorgestrel is bound to serum albumin and to SHBG. Only 1.4% of the total serum drug levels are present as free steroid, but 55% 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 fractions decrease.

Following daily repeated administration of Logynon ED, levonorgestrel concentrations in the serum increase by a factor of about 4. Steady-state conditions are reached during the second half of a treatment cycle. The pharmacokinetics of levonorgestrel is influenced by SHBG serum levels. Under treatment with Logynon ED, an increase in the serum levels of SHBG by a factor of about 2 occurs during a treatment cycle. Due to the specific binding of levonorgestrel to SHBG, the increase in SHBG levels is accompanied by an almost parallel increase in levonorgestrel serum levels. The absolute bioavailability of levonorgestrel was determined to be almost 100% of the dose administered.

Ethinylestradiol

Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of 0.03mg ethinylestradiol together with 0.125mg levonorgestrel, maximum drug serum levels of about 116 pg/ml are reached at 1.3 hours. Thereafter, ethinylestradiol serum levels decrease in two phases characterized by half-lives of 1 - 2 hours and about 20 hours. For technical 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 5 ml/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.

Due 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. The absolute bioavailability of ethinylestradiol is subject to a considerable interindividual variation. Following oral administration, the mean bioavailability was found to be about 40 - 60% of the administered 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 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 Logynon ED, SHBG concentrations in the serum increased from about 76 nmol/l to 164 nmol/l and the serum concentrations of CBG increased from about 48 μg/ml to 111 μg/ml.

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.

Excipients included in both active and placebo tablets:

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:

Cartons containing 3 blister memo-packs. Each memo-pack contains 21 active tablets and 7 placebo tablets (total 28 tablets).

No special requirements.

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

Trading as Bayer plc, Bayer Schering Pharma

00010/0541

06 March 2009

18 July 2011