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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Norimin

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 milligram Norethisterone and 35 micrograms Ethinylestradiol.

3 PHARMACEUTICAL FORM

White round, flat tablets with bevel-edges inscribed 'SEARLE' on one side and 'BX' on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Norimin is indicated for oral contraception, with the benefit of a low intake of oestrogen.

4.2 Posology and method of administration

Oral administration: The dosage of Norimin for the initial cycle of therapy is 1 tablet taken at the same time each day from the first day of the menstrual cycle. For subsequent cycles, no tablets are taken for 7 days, then a new course is started of 1 tablet daily for the next 21 days. This sequence of 21 days on treatment, seven days off treatment is repeated for as long as contraception is required.

Patients unable to start taking Norimin tablets on the first day of the menstrual cycle may start treatment on any day up to and including the 5th day of the menstrual cycle.

Patients starting on day 1 of their period will be protected at once. Those patients delaying therapy up to day 5 may not be protected immediately and it is recommended that another method of contraception is used for the first 7 days of tablet taking. Suitable methods are condoms, caps plus spermicides and intra-uterine devices. The rhythm, temperature and cervical-mucus methods should not be relied upon.

Tablet omissions.

Tablets must be taken daily in order to maintain adequate hormone levels and contraceptive efficacy.

If a tablet is missed within 12 hours of the correct dosage time then the missed tablet should be taken as soon as possible, even if this means taking 2 tablets on the same day, this will ensure that contraceptive protection is maintained. If one or more tablets are missed for more than 12 hours from the correct dosage time it is recommended that the patient takes the last missed tablet as soon as possible and then continues to take the rest of the tablets in the normal manner. In addition, it is recommended that extra contraceptive protection, such as a condom, is used for the next 7 days.

Patients who have missed one or more of the last 7 tablets in a pack should be advised to start the next pack of tablets as soon as the present one has finished (i.e. without the normal seven day gap between treatments). This reduces the risk of contraceptive failure resulting from tablets being missed close to a 7 day tablet free period.

Changing from another oral contraceptive.

In order to ensure that contraception is maintained it is advised that the first dose of Norimin tablets is taken on the day immediately after the patient has finished the previous pack of tablets.

Use after childbirth, miscarriage or abortion.

Providing the patient is not breast feeding the first dose of Norimin tablets should be taken on the 21st day after childbirth. This will ensure the patient is protected immediately. If there is any delay in taking the first dose, contraception may not be established until 7 days after the first tablet has been taken. In these circumstances patients should be advised that extra contraceptive methods will be necessary.

After a miscarriage or abortion patients can take the first dose of Norimin tablets on the next day; in this way they will be protected immediately.

4.3 Contraindications

As with all combined progestogen/oestrogen oral contraceptives, the following

conditions should be regarded as contra-indications :

(i)    History of confirmed venous thromboembolic disease (VTE), family history of idiopathic VTE and other known risk factors of VTE.

(ii)    Thrombophlebitis, cerebrovascular disorders, coronary artery disease, myocardial infarction, angina, hyperlipidaemia or a history of these conditions.

(iii)    Acute or severe chronic liver disease, including liver tumours, Dubin-Johnson or Rotor syndrome.

(iv)    History during pregnancy of idiopathic jaundice, severe pruritus or pemphigoid gestations.

(v)    Known or suspected breast or genital cancer.

(vi)    Known or suspected oestrogen-dependent neoplasia.

(vii)    Undiagnosed abnormal vaginal bleeding.

(viii)    A history of migraines classified as classical focal or crescendo.

(ix)    Pregnancy.

4.4 Special warnings and precautions for use

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.

Women taking oral contraceptives require careful observation if they have or have had any of the following conditions: breast nodules; fibrocystic disease of the breast or an abnormal mammogram; uterine fibroids; a history of severe depressive states; varicose veins; sickle-cell anaemia; diabetes; hypertension; cardiovascular disease; migraine; epilepsy; asthma; otosclerosis; multiple sclerosis; porphyria; tetany; disturbed liver functions; gallstones; kidney disease; chloasma; any condition that is likely to worsen during pregnancy. The worsening or first appearance of any of these conditions may indicate that the oral contraceptive should be stopped. Discontinue treatment if there is a gradual or sudden, partial or complete loss of vision or any evidence of ocular changes, onset or aggravation of migraine or development of headache of a new kind which is recurrent, persistent or severe.

Gastro-intestinal upsets, such as vomiting and diarrhoea, may interfere with the absorption of the tablets leading to a reduction in contraceptive efficacy. Patients should continue to take Norimin, but they should also be encouraged to use another contraceptive method during the period of gastro-intestinal upset and for the next 7 days.

Progestogen oestrogen preparations should be used with caution in patients with a history of hepatic dysfunction or hypertension.

An increased risk of venous thromboembolic 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 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.

Patients receiving oral contraceptives should be kept under regular surveillance, in view of the possibility of development of conditions such as thrombo-embolism.

The risk of coronary artery disease in women taking oral contraceptives is increased by the presence of other predisposing factors such as cigarette smoking, hypercholesterolaemia, obesity, diabetes, history of pre-eclamptic toxaemia and increasing age. After the age of thirty-five years, the patient and physician should carefully re-assess the risk/benefit ratio of using combined oral contraceptives as opposed to alternative methods of contraception.

Norimin should be discontinued at least four weeks before, and for two weeks following, elective operations and during immobilisation. Patients undergoing injection treatment for varicose veins should not resume taking Norimin until 3 months after the last injection.

Benign and malignant liver tumours have been associated with oral contraceptive use. The relationship between occurrence of liver tumours and use of female sex hormones is not known at present. These tumours may rupture causing intra-abdominal bleeding. If the patient presents with a mass or tenderness in the right upper quadrant or an acute abdomen, the possible presence of a tumour should be considered.

An increased risk of congenital abnormalities including heart defects and limb defects, has been reported following the use of sex hormones, including oral contraceptives, in pregnancy. If the patient does not adhere to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and further use of oral contraceptives should be withheld until pregnancy has been ruled out. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. If pregnancy is confirmed the patient should be advised of the potential risks to the foetus and the advisability of continuing the pregnancy should be discussed in the light of these risks. It is advisable to discontinue Norimin three months before a planned pregnancy.

The risk of arterial thrombosis associated with combined oral contraceptives increases with age, and this risk is aggravated by cigarette smoking. The use of combined oral contraceptives by women in the older age group, especially those who are cigarette smokers, should therefore be discouraged and alternative methods advised.

The use of this product in patients suffering from epilepsy, migraine, asthma or cardiac dysfunction may result in exacerbation of these disorders because of fluid retention. Caution should also be observed in patients who wear contact lenses.

Decreased glucose tolerance may occur in diabetic patients on this treatment, and their control must be carefully supervised.

The use of oral contraceptives has also been associated with a possible increased incidence of gall bladder disease.

Women with a history of oligomenorrhoea or secondary amenorrhoea or young women without regular cycles may have a tendency to remain anovulatory or to become amenorrhoeic after discontinuation of oral contraceptives. Women with these pre-existing problems should be advised of this possibility and encouraged to use other contraceptive methods.

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

300

4.5 Interaction with other medicinal products and other forms of interaction

The herbal remedy St John’s wort (Hypericumperforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect.

Some drugs may modify the metabolism of Norimin reducing its effectiveness; these include certain sedatives, antibiotics, anti-epileptic and anti-arthritic drugs. During the time such agents are used concurrently, it is advised that mechanical contraceptives also be used.

The results of a large number of laboratory tests have been shown to be influenced by the use of oestrogen containing oral contraceptives, which may limit their diagnostic value. Among these are: biochemical markers of thyroid and liver function; plasma levels of carrier proteins, triglycerides, coagulation and fibrinolysis factors.

4.6 Fertility, Pregnancy and lactation

Contra-indicated in pregnancy.

Patients who are fully breast-feeding should not take Norimin tablets since, in common with other combined oral contraceptives, the oestrogen component may reduce the amount of milk produced. In addition, active ingredients or their metabolites have been detected in the milk of mothers taking oral contraceptives. The effect of Norimin on breast-fed infants has not been determined.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

As with all oral contraceptives, there may be slight nausea at first, weight gain or breast discomfort, which soon disappear.

Other side-effects known or suspected to occur with oral contraceptives include gastro-intestinal symptoms, changes in libido and appetite, headache, exacerbation of existing uterine fibroid disease, depression and changes in carbohydrate, lipid and vitamin metabolism.

Spotting or bleeding may occur during the first few cycles. Usually menstrual bleeding becomes light and occasionally there may be no bleeding during the tablet-free days.

Hypertension, which is usually reversible on discontinuing treatment, has occurred in a small percentage of women taking oral contraceptives.

4.9 Overdose

Overdosage may be manifested by nausea, vomiting, breast enlargement and vaginal bleeding. There is no specific antidote and treatment should be symptomatic. Gastric lavage may be employed if the overdose is large and the patient is seen sufficiently early (within four hours).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The mode of action of Norimin is similar to that of other progestogen/oestrogen oral contraceptives and includes the inhibition of ovulation, the thickening of cervical mucus so as to constitute a barrier to sperm and the rendering of the endometrium unreceptive to implantation. Such activity is exerted through a combined effect on one or more of the following: hypothalamus, anterior pituitary, ovary, endometrium and cervical mucus.

5.2 Pharmacokinetic properties

Norethisterone is rapidly and completely absorbed after oral administration, peak plasma concentrations occurring in the majority of subjects between 1 and 3 hours. Due to first-pass metabolism, blood levels after oral administration are 60% of those after i.v. administration. The half life of elimination varies from 5 to 12 hours, with a mean of 7.6 hours. Norethisterone is metabolised mainly in the liver. Approximately 60% of the administered dose is excreted as metabolites in urine and faeces.

Ethinylestradiol is rapidly and well absorbed from the gastro-intestinal tract but is subject to some first-pass metabolism in the gut-wall. Compared to many other oestrogens it is only slowly metabolised in the liver. Excretion is via the kidneys with some appearing also in the faeces.

5.3 Preclinical safety data

The toxicity of norethisterone is very low. Reports of teratogenic effects in animals are uncommon. No carcinogenic effects have been found even in long-term studies.

Long-term continuous administration of oestrogens in some animals increases the frequency of carcinoma of the breast, cervix, vagina and liver.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Norimin tablets contain:

Maize starch, polyvidone, magnesium stearate and lactose.

6.2    Incompatibilities

None stated.

6.3    Shelf life

The shelf life of Norimin tablets is 5 years.

6.4    Special precautions for storage

Store in a dry place, below 25°C, away from direct sunlight.