BINOVUM^® Oral Contraceptive Tablets.

For a full list of excipients, see section 6.1.

Tablets.

Contraception and the recognised indications for such oestrogen/progestogen combinations.

Adults

It is preferable that tablet intake from the first pack is started on the first day of menstruation in which case no extra contraceptive precautions are necessary.

If menstruation has already begun (that is 2, 3 or 4 days previously), tablet taking should commence on day 5 of the menstrual period. In this case, additional contraceptive precautions must be taken for the first 7 days of tablet taking.

If menstruation began more than 5 days previously then the patient should be advised to wait until her next menstrual period before starting to take Binovum.

How to take Binovum:

One tablet is taken daily at the same time (preferably in the evening) without interruption for 21 days, followed by a break of 7 tablet-free days. (A white tablet is taken every day for 7 days, then a peach coloured tablet is taken every day for 14 days, then 7 tablet-free days). Each subsequent pack is started after the 7 tablet-free days have elapsed. Additional contraceptive precautions are not then required.

Elderly:

Not applicable.

Children:

Not recommended.

Absolute contra-indications

− Pregnancy or suspected pregnancy (that cannot yet be excluded).

− Circulatory disorders (cardiovascular or cerebrovascular) such as thrombophlebitis and thrombo-embolic processes, or a history of these conditions (including history of confirmed venous thrombo-embolism (VTE), family history of idiopathic VTE and other known risk factors for VTE), moderate to severe hypertension, hyperlipoproteinaemia. In addition, the presence of more than one of the risk factors for arterial disease.

− Severe liver disease, cholestatic jaundice or hepatitis (viral or non-viral) or a history of these conditions if the results of liver function tests have failed to return to normal, and for 3 months after liver function tests have been found to be normal; a history of jaundice of pregnancy or jaundice due to the use of steroids, Rotor syndrome and Dubin-Johnson syndrome, hepatic cell tumours and porphyria.

− Cholelithiasis.

− Known or suspected oestrogen-dependent tumours; endometrial hyperplasia; undiagnosed vaginal bleeding.

− Systemic lupus erythematosus or a history of this condition.

− A history during pregnancy or previous use of steroids of:

• severe pruritus

• herpes gestationis

• a manifestation or deterioration of otosclerosis

Relative contra-indications:

If any relative contra-indication listed below are present, the benefits of oestrogen/progestogen containing preparations must be weighed against the possible risk for each individual case and the patient kept under close supervision. In case of aggravation or appearance of any of these conditions whilst the patient is taking the pill, its use should be discontinued.

− Conditions implicating an increasing risk of developing venous thrombo-embolic complications, eg severe varicose veins or prolonged immobilisation or major surgery.

− Disorders of coagulation.

− Presence of any risk factor for arterial disease e.g. smoking, hyperlipidaemia or hypertension.

− Other conditions associated with an increased risk of circulatory disease such as latent or overt cardiac failure, renal dysfunction, or a history of these conditions.

− Epilepsy or a history of this condition.

− Migraine or a history of this condition.

− A history of cholelithiasis.

− Presence of any risk factor for oestrogen-dependent tumours; oestrogen-sensitive gynaecological disorders such as uterine fibromyomata and endometriosis.

− Diabetes mellitus.

− Severe depression or a history of this condition. If this is accompanied by a disturbance in tryptophan metabolism, administration of vitamin B6 might be of therapeutic value.

− Sickle cell haemoglobinopathy, since under certain circumstances, e.g. during infections or anoxia, oestrogen containing preparations may induce thrombo-embolic process in patients with this condition.

− If the results of liver function tests become abnormal, use should be discontinued.

Post partum administration

Following a vaginal delivery, oral contraceptive administration to non-breast-feeding mothers can be started 21 days post-partum provided the patient is fully ambulant and there are no puerperal complications. No additional contraceptive precautions are required. If post partum administration begins more than 21 days after delivery, additional contraceptive precautions are required for the first 7 days of pill-taking.

If intercourse has taken place post-partum, oral contraceptive use should be delayed until the first day of the first menstrual period.

After miscarriage or abortion, administration should start immediately, in which case no additional contraceptive precautions are required.

Changing from a 21 day pill or 22 day pill to Binovum

All tablets in the old pack should be finished. The first Binovum tablet is taken the next day i.e. no gap is left between taking tablets nor does the patient need to wait for her period to begin. Tablets should be taken as instructed in 'How to take Binovum' (see 4.2). Additional contraceptive precautions are not required. The patient will not have a period until the end of the first Binovum pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

Changing from a combined every day pill (28 day tablet) to Binovum

Binovum should be started after taking the last active tablet from the 'Every day Pill' pack (ie after taking 21 or 22 tablets). The first Binovum tablet is taken the next day, ie no gap is left between taking tablets nor does the patient need to wait for her period to begin. Tablets should be taken as instructed in 'How to take Binovum' (see 4.2). Additional contraceptive precautions are not required. Remaining tablets from the every day (ED) pack should be discarded.

The patient will not have a period until the end of the first Binovum pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

Changing from a progestogen-only pill (POP or mini pill) to Binovum

The first Binovum tablet should be taken on the first day of the period, even if the patient has already taken a mini pill on that day. Tablets should be taken as instructed in 'How to take Binovum' (see 4.2). Additional contraceptive precautions are not required. All the remaining progestogen-only pills in the mini pill pack should be discarded.

If the patient is taking a mini pill, then she may not always have a period, especially when she is breast-feeding. The first Binovum tablet should be taken on the day after stopping the mini pill. All remaining pills in the mini pill packet must be discarded. Additional contraceptive precautions must be taken for the first 7 days.

To skip a period

To skip a period, a new pack of Binovum should be started on the day after finishing the current pack (the patient skips the tablet-free days). Tablet-taking should be continued in the usual way.

During the use of the second pack, she may experience slight spotting or break-through bleeding but contraceptive protection will not be diminished provided there are no tablet omissions.

The next pack of Binovum is started after the usual 7 tablet-free days, regardless of whether the period has completely finished or not.

Reduced reliability

When Binovum is taken according to the directions for use the occurrence of pregnancy is highly unlikely. However the reliability of oral contraceptives may be reduced under the following circumstances:

i) Forgotten tablets

If the patient forgets to take a tablet, she should take it as soon as she remembers and take the next one at the normal time. This may mean that two tablets are taken in one day. Provided she is less than 12 hours late in taking her tablet, Binovum will still give contraceptive protection during this cycle and the rest of the pack should be taken as usual.

If she is more than 12 hours late in taking one or more tablets, then she should take the last missed pill as soon as she remembers but leave the other missed pills in the pack. She should continue to take the rest of the pack as usual but must use extra precautions (e.g. sheath, diaphragm, plus spermicide) and follow the '7-day rule' (see Further Information for the '7 day rule').

If there are 7 or more pills left in the pack after the missed and delayed pills then the usual 7-day break can be left before starting the next pack. If there are less than 7 pills left in the pack after the missed and delayed pills then when the pack is finished the next pack should be started the next day. If withdrawal bleeding does not occur at the end of the second pack then a pregnancy test should be performed.

ii) Vomiting or diarrhoea

If after tablet intake, vomiting or diarrhoea occurs, a tablet may not be absorbed properly by the body. If the symptoms disappear within 12 hours of tablet-taking, the patient should take an extra tablet from a spare pack and continue with the rest of the pack as usual.

However, if the symptoms continue beyond those 12 hours, additional contraceptive precautions are necessary for any sexual intercourse during the stomach or bowel upset and for the following 7 days (the patient must be advised to follow the '7-day rule').

iii) Change in bleeding pattern

If after taking Binovum for several months there is a sudden occurrence of spotting or breakthrough bleeding (not observed in previous cycles) or the absence of withdrawal bleeding, contraceptive effectiveness may be reduced. If withdrawal bleeding fails to occur and none of the above mentioned events has taken place, pregnancy is highly unlikely and oral contraceptive use can be continued until the end of the next pack. (If withdrawal bleeding fails to occur at the end of the second cycle, tablet intake should be discontinued and pregnancy excluded before oral contraceptive use can be resumed.) However, if withdrawal bleeding is absent and any of the above mentioned events has occurred, tablet intake should be discontinued and pregnancy excluded before oral contraceptive use can be resumed.

Medical examination/consultation

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 contra-indications (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.

Caution should be observed when prescribing oral contraceptives to young women whose cycles are not yet stabilised.

Venous thrombo-embolic disease

An increased risk of venous thrombo-embolic disease (VTE) associated with the use of oral contraceptives is well established but is smaller than that associated with pregnancy, which has been estimated at 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 or norethisterone (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 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 excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive.

Surgery, varicose veins or immobilisation

In patients using oestrogen-containing preparations, the risk of deep vein thrombosis may be temporarily increased when undergoing a major operation (eg abdominal, orthopaedic), and surgery to the legs, medical treatment for varicose veins or prolonged immobilisation. Therefore, it is advisable to discontinue oral contraceptive use at least 4 to 6 weeks prior to these procedures if performed electively and to (re)start not less than 2 weeks after full ambulation. The latter is also valid with regard to immobilisation after an accident or emergency surgery. In case of emergency surgery, thrombotic prophylaxis is usually indicated, eg with subcutaneous heparin.

Chloasma

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 this preparation. Chloasma is often not fully reversible.

Laboratory tests

The use of steroids may influence the results of certain laboratory tests. In the literature, at least a hundred different parameters have been reported to possibly be influenced by oral contraceptive use, predominantly by the oestrogenic component. Among these are: biochemical parameters of the liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins and lipid/lipoprotein fractions and parameters of coagulation and fibrinolysis.

Further information

Additional contraceptive precautions

When additional contraceptive precautions are required, the patient should be advised either not to have sex, or to use a cap plus spermicide or for her partner to use a condom. Rhythm methods should not be advised as the pill disrupts the usual cyclical changes associated with the natural menstrual cycle, eg changes in temperature and cervical mucus.

The 7-day rule

If any one tablet is forgotten for more than 12 hours.

If the patient has vomiting or diarrhoea for more than 12 hours.

If the patient is taking any of the drugs listed under 'Interactions'.

The patient should continue to take her tablets as usual and:

− Additional contraceptive precautions must be taken for the next 7 days.

But - if these 7 days run beyond the end of the current pack, the next pack must be started as soon as the current one is finished, ie no gap should be left between packs. (This prevents an extended break in tablet taking which may increase the risk of the ovaries releasing an egg and thus reducing contraceptive protection.) The patient will not have a period until the end of 2 packs but this is not harmful nor does it matter if she experiences some bleeding on tablet taking days.

Irregular cycles and reduced reliability of oral contraceptives may occur when these preparations are used concomitantly with drugs such as anticonvulsants, barbiturates, antibiotics (eg tetracyclines, ampicillin, rifampicin, etc), griseofulvin, activated charcoal and certain laxatives. Special consideration should be given to patients being treated with antibiotics for acne. They should be advised to use a non-hormonal method of contraception, or to use an oral contraceptive containing a progestogen showing minimal androgenicity, which have been reported as helping to improve acne without using an antibiotic. Oral contraceptives may diminish glucose tolerance and increase the need for insulin or other antidiabetic drugs in diabetics.

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

Binovum is contra-indicated for use during pregnancy or suspected pregnancy, since it has been suggested that combined oral contraceptives, in common with many other substances, might be capable of affecting the normal development of the child in the early stages of pregnancy. It can be concluded, however, that, if a risk of abnormality exists at all, it must be very small.

Mothers who are breast-feeding should be advised not to use the combined pill since this may reduce the amount of breast milk, but may be advised instead to use a progestogen-only pill (POP).

Not applicable.

Various adverse reactions have been associated with oral contraceptive use. The first appearance of symptoms indicative of any one of these reactions necessitates immediate cessation of oral contraceptive use while appropriate diagnostic and therapeutic measures are undertaken.

Serious Adverse Reactions

− There is a general opinion, based on statistical evidence that users of combined oral contraceptives experience more often than non-users, various disorders of the coagulation. How often these disorders occur in users of modern low-oestrogen oral contraceptives is unknown, but there are reasons for suggesting that they may occur less often than with the older types of pill which contain more oestrogen.

Various reports have associated oral contraceptive use with the occurrence of deep venous thrombosis, pulmonary embolism and other embolisms. Other investigations of these oral contraceptives have suggested an increased risk of oestrogen and/or progestogen dose-dependent coronary and cerebrovascular accidents, predominantly in heavy smokers. Thrombosis has very rarely been reported to occur in other veins or arteries, eg hepatic, mesenteric, renal or retinal.

It should be noted that there is no consensus about often contradictory findings obtained in early studies. The physician should bear in mind the possibility of vascular accidents occurring and that there may not be full recovery from such disorders and they may be fatal. The physician should take into account the presence of risk factors for arterial disease and deep venous thrombosis when prescribing oral contraceptives. Risk factors for arterial disease include smoking, the presence of hyperlipidaemia, hypertension or diabetes.

Signs and symptoms of a thrombotic event may include: sudden severe pain in the chest, whether or not reaching to the left arm; sudden breathlessness; and unusual severe, prolonged headache, especially if it occurs for the first time or gets progressively worse, or is associated with any of the following symptoms: sudden partial or complete loss of vision or diplopia, aphasia, vertigo, a bad fainting attack or collapse with or without focal epilepsy, weakness or very marked numbness suddenly affecting one side or one part of the body, motor disturbances; severe pain in the calf of one leg; acute abdomen.

Cigarette smoking increases the risk of serious cardiovascular adverse reactions to oral contraceptive use. The risk increases with age and with heavy smoking and is more marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

− The use of oestrogen-containing oral contraceptives may promote growth of existing sex steroid dependent tumours. For this reason, the use of these oral contraceptives in patients with such tumours is contra-indicated. Numerous epidemiological studies have been reported on the risk 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 10 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 (eg ovarian and endometrial cancer).

− Malignant hepatic tumours have been reported on rare occasions in long-term users of oral contraceptives. Benign hepatic tumours have also been associated with oral contraceptive usage. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur.

− The use of oral contraceptives may sometimes lead to the development of cholestatic jaundice or cholelithiasis.

− On rare occasions the use of oral contraceptives may trigger or reactivate systemic lupus erythematosus.

− A further rare complication of oral contraceptive use is the occurrence of chorea which can be reversed by discontinuing the pill. The majority of cases of oral contraceptive-induced chorea show a pre-existing predisposition which often relates to acute rheumatism.

Other Adverse Reactions

−Cardiovascular System

Rise of blood pressure. If hypertension develops, treatment should be discontinued.

−Genital Tract

Intermenstrual bleeding, post-medication amenorrhoea, changes in cervical secretion, increase in size of uterine fibromyomata, aggravation of endometriosis, certain vaginal infections, eg candidosis.

−Breast

Tenderness, pain, enlargement, secretion.

−Gastro-intestinal Tract

Nausea, vomiting, cholelithiasis, cholestatic jaundice.

−Skin

Erythema nodosum, rash, chloasma, erythema multiforme, hirsutism, loss of scalp hair.

−Eyes

Discomfort of the cornea if contact lenses are used.

−CNS

Headache, migraine, mood changes, depression.

−Metabolic

Fluid retention, change in body weight, reduced glucose tolerance.

−Other

Changes in libido, leg cramp, premenstrual-like syndrome.

There have been no reports of serious ill-health from overdosage even when a considerable number of tablets has been taken by a small child. In general, it is therefore unnecessary to treat overdosage. However, if overdosage is discovered within two or three hours and is large, then gastric lavage can be safely used. There are no antidotes and further treatment should be symptomatic.

Binovum Oral Contraceptive Tablets act through the mechanism of gonadotrophin suppression by the oestrogenic and progestational actions of the ethinylestradiol and norethisterone. The primary mechanism of action is inhibition of ovulation, but alterations to the cervical mucus and to the endometrium may also contribute to the efficacy of the product.

Norethisterone and ethinylestradiol are absorbed from the gastro-intestinal tract and metabolised in the liver. To obtain maximal contraceptive effectiveness, the tablets should be taken as directed and at approximately the same time each day.

Because the active ingredients are metabolised in the liver, reduced contraceptive efficacy has been associated with concomitant use of oral contraceptives and rifampicin. A similar association has been suggested with oral contraceptives and barbiturates, phenytoin sodium, phenylbutazone, griseofulvin and ampicillin.

The toxicology of norethisterone and ethinylestradiol has been extensively investigated in animal studies and through long term clinical experience with widespread use in contraceptives.

White Tablets:

Magnesium Stearate

Pregelatinised Starch

Lactose

Methanol

Peach Coloured Tablets:

Magnesium Stearate

Pregelatinised Starch

Lactose

FD & C Yellow No.6

Methanol

Purified water

Not applicable.

Two years

Do not store above 30°C. Protect from light.

Clear, uncoloured PVC/foil blister strips in a cardboard carton.

Cartons containing 1 (starter pack)*, 3, and 50* PVC/foil blister strips of 21 tablets each..

*Non-marketed pack sizes.

Not applicable.

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PL 0242/0208

23 February 2009

23 February 2009