SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Micronor Oral Contraceptive Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains norethisterone 0.35 mg.

3 PHARMACEUTICAL FORM

Small, round, white tablet, engraved C035 on both faces.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Oral contraceptive.

4.2 Posology and method of administration

For oral administration.

4.2.1 Adults

How to take Micronor:

Tablet intake from the first pack is started on day 1 up to and including day 5 of the menstrual cycle; no extra contraceptive precautions are necessary.

One tablet is taken at the same time each day, every day of the year, whether menstruation occurs or not.

Starting treatment

It is preferable that tablet intake from the first pack is started up to and including day 5 of menstruation in which case no extra contraceptive precautions are necessary.

Micronor can be started at any other time, if pregnancy can reasonably be excluded. In this case, additional contraceptive precautions must be taken for the first 48 hours of tablet taking.

If the patient is amenorrhoeic, pregnancy should be excluded prior to starting Micronor and there is no risk of conception. In this case additional contraceptive precautions must be taken for the first 48 hours of tablet taking.

Switching from another contraceptive

Combined oral Contraceptive (CoC), Progestogen-only Pill (POP), Progestogen-only implant: Micronor can be started immediately if the patient has been using the current hormonal method consistently and correctly, or if pregnancy can reasonably be excluded. There is no need to wait for the next menstruation. Additional contraceptive precautions are not required.

Progestogen-only injectable:Micronor can be started when the repeat injection would have been given, or before. Additional contraceptive precautions are not required.

IUDs: Start Micronor at least 2 days before the removal of the IUD. Additional contraceptive precautions are not required. However, if it is started at the time of removal, the patient should avoid intercourse or use another non-hormonal contraceptive (e.g. condoms) for 7 days before removal if possible and take extra contraceptive precautions for 48 hours after starting Micronor.

Levonorgesterel-releasing IUS: Micronor can be started when the IUS is removed. Additional contraceptive precautions are not required.

Post-partum administration

Following a vaginal delivery, Micronor can be started immediately. 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 48 hours of tablet taking.

Use after Abortion or Miscarriage

Micronor can be started immediately. An additional method of contraception is not needed.

If tablet taking is started more than 1 day after surgical abortion, second part of medical abortion or miscarriage, additional contraceptive precautions must be taken for the first 48 hours of tablet taking.

Reduced reliability

When Micronor 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)    Missed or late tablets

If a tablet is missed within 3 hours of the correct dosage time, then the missed tablet should be taken as soon as possible; this will ensure that contraceptive protection is maintained. If one (for longer than 3 hours) or more tablets are missed, it is recommended that the patient takes the last missed tablet as soon as possible and continues to take the rest of the tablets as usual. This may mean taking two tablets in one day. Additional means of contraception (non-hormonal) should be used for the next 48 hours.

If the patient does not have a period within 45 days of her last period, Micronor should be discontinued and pregnancy should be excluded.

(ii)    Vomiting and diarrhoea

If vomiting occurs within 3 hours of taking a tablet, the patient should take another tablet as soon as possible. If vomiting and/or diarrhoea continue for more than 3 hours after taking a tablet, or if severe diarrhoea lasts for more than 24 hours, the effectiveness of the contraception may not be adequate, and an additional nonhormonal method of contraception should be used for 48 hours without interruption.

4.2.2    Children

Use of this product before menarche is not indicated.

4.2.3    Elderly

Use of this product is not indicated in post-menopausal women.

4.3 Contraindications

•    Known or suspected carcinoma of the breast.

•    Hypersensitivity to norethisterone or to any of the excipients.

4.4 Special warnings and precautions for use

There is a general opinion, based on statistical evidence, that users of combined oral contraceptives (ie oestrogen plus progestogen) experience more often than non-users various disorders of the circulation of blood, including strokes (blood clots in, and haemorrhages from, the blood vessels of the brain), heart attacks (coronary thromboses) and blood clots obstructing the arteries of the lungs (pulmonary emboli). There may not be a full recovery from such disorders and it should be realised that in a few cases they may be fatal.

To date no association between these disorders and progestogen-only oral contraceptives (such as Micronor Oral Contraceptive Tablets) has been shown. However there is a risk that the users of such progestogen-only oral contraceptives will (like users of the combined oral contraceptive) be exposed to an increased risk of suffering from these disorders.

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 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.

Exclude likelihood of pregnancy before starting treatment.

In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.

Oral contraceptives DO NOT protect against HIV infections (AIDS) or any other sexually transmitted disease.

Because of a possible increased risk of post surgery thrombo-embolic complications in oral contraceptive users, therapy should be discontinued six weeks prior to elective surgery.

When Micronor is administered during the post-partum period, the increased risk of thrombo-embolic disease associated with the post-partum period must be considered.

Conditions requiring supervision

The theoretical or proven risks usually outweigh the advantages of using POPs in the conditions listed below. Consequently the decision to prescribe the POP must be made with specialist clinical judgement and in consultation with the individual patient.

•    A history of breast cancer with no evidence of disease in the last 5 years

•    Severe decompensated cirrhosis

• Liver tumours (benign and malignant)

•    Acute or chronic hepatocellular disease with abnormal liver function

•    Systemic Lupus Erythematosus (SLE) with antiphospholipid antibodies

•    Current or history of ischaemic heart disease

•    History of cerebrovascular accidents, including transient ischaemic attacks

•    Porphyria

The worsening or first appearance of any of these conditions may indicate that Micronor should be discontinued.

Ectopic pregnancy

The incidence of ectopic pregnancies for progestogen-only oral contraceptive users is 5 per 1000 woman-years, which is higher than for women using other contraceptive methods but similar to the incidence for women not using any contraception. Up to 10% of pregnancies reported in clinical studies of progestogen-only oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, a history of ectopic pregnancy need not be considered a contraindication to use of this contraceptive method. Vaginal bleeding and abdominal pain are typical symptoms of an ectopic pregnancy. Women reporting these symptoms should be evaluated.

Carcinomas

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives.

Breast cancer

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk of having breast cancer diagnosed in women who are currently using oral contraceptives (OCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in OC users, the biological effects of OCs or a combination of both. The additional breast cancers diagnosed in current users of OCs or in women who have used OCs in the last 10 years are more likely to be localised to the breast than those in women who have never used OCs.

Breast cancer is rare among women under 40 years of age whether or not they take OCs. Whilst the background risk increases with age, the excess number of breast cancer diagnoses in current and recent progesterone-only pill (POP) users is small in relation to the overall risk of breast cancer, possibly of similar magnitude to that associated with combined OCs. However, for POPs, the evidence is based on much smaller populations of users and so is less conclusive than that for combined OCs.

The most important risk factor for breast cancer in POP users is the age women discontinue the POP; 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 POP use, such that by 10 years there appears to be no excess.

The evidence suggests that compared with never-users, among 10,000 women who use POPs for up to five years but stop by age 20, there would be much less than one extra case of breast cancer diagnosed up to 10 years afterwards. For those stopping by age 30 after 5 years use of the POP, there would be an estimated 2-3 extra cases (additional to the 44 cases of breast cancer per 10,000 women in this age group never exposed to oral contraceptives). For those stopping by age 40 after 5 years use, there would be an estimated 10 extra cases diagnosed up to 10 years afterwards (additional to the 160 cases of breast cancer per 10,000 never-exposed women in this age group).

It is important to inform patients that users of all contraceptive pills appear to have a small increase in the risk of being diagnosed with breast cancer, compared with nonusers of oral contraceptives, but that this has to be weighed against the known benefits.

Cervical cancer

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behaviour and other factors. There is insufficient data to determine whether the use of POPs increases the risk of developing cervical intraepithelial neoplasia.

Hepatic neoplasia

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 use. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur.

Carbohydrate and lipid metabolism

Carbohydrate changes in healthy individuals from clinical studies are mixed. Most studies show no effect, but in some studies there is a suggestion of slight deterioration in glucose tolerance and elevation in plasma insulin concentration. From the limited data on POPs in diabetic women, no increase in insulin dose was required.

Delayed follicular atresia/ovarian cysts

If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle.

Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases they are associated with mild abdominal pain. Rarely they may twist or rupture, requiring surgical intervention.

Bleeding irregularities

Irregular menstrual patterns are common among women using progestogen-only oral contraceptives. If genital bleeding is suggestive of infection, malignancy or other abnormal conditions, such non-pharmacologic causes should be ruled out. If prolonged amenorrhea occurs, the possibility of pregnancy should be evaluated.

Headache

The onset or exacerbation of migraine or development of headache with a new pattern, which is recurrent, persistent or severe, requires discontinuation of oral contraceptives and evaluation of the cause should be considered.

Other conditions and warnings

In the following conditions the benefit of oral contraception generally outweighs the theoretical or known risk. However, they may need to be considered before prescribing to individual patients or continuing treatment if they arise:

•    Multiple risk factors for cardiovascular disease (including older age, smoking, diabetes, hypertension and obesity)

•    Vascular disease (including coronary heart disease with angina, peripheral vascular disease with intermittent claudication, hypertensive retinopathy)History of venous thrombo-embolism (VTE) or current VTE

•    Major surgery with prolonged immobilisation

•    Known thrombogenic mutations (such as Factor V Leiden, Prothrombin mutation, Protein S, Protein C and Antithrombin deficiencies

•    Migraine with or without focal aura at any age or a past history (>5 years ago). The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires evaluation of the cause

•    Carriers of known gene mutations associated with breast cancer (e.g. BRCA1)

•    Diabetes with or without vascular involvement (although all patients with diabetes are at increased risk of arterial disease)

•    Known hyperlipidaemias. However, routine screening of women with is not considered appropriate

•    Gall bladder disease

•    History of cholestasis related to past COC use

•    Benign liver tumour (focal nodular hyperplasia)

•    Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis)

•    Raynaud’s disease secondary with Systemic Lupus Erythematosus (SLE) if lupus anticoagulant is present.

Laboratory tests

Certain endocrine and liver function tests and blood components may be affected by progestogen-only oral contraceptive use:

•    Sex hormone-binding globulin (SHBG) concentrations may be decreased

•    Thyroxine concentrations may be decreased, due to a decrease in thyroid binding globulin (TBG).

Excipients

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Potential Reduction in Contraceptive Effectiveness Associated With CoAdministration of Other Drugs:

Hepatic enzyme inducers

Drugs or herbal products that induce enzymes, especially CYP3A4, may decrease the plasma concentrations of norethisterone, and may decrease its effectiveness and/or increase breakthrough bleeding.

Examples include:

•    some anti-epileptics (e.g. carbamazepine, phenytoin)

•    (fos)aprepitant

•    barbiturates

•    bosentan

•    griseofulvin

•    some (combinations of)    HIV    protease    inhibitors    (e.g. nelfinavir,    some

ritonavir-boosted protease inhibitors, darunavir/ritonavir, lopinavir/ritonavir)

•    some non-nucleoside reverse    transcriptase inhibitors (e.g. nevirapine)

•    rifampicin and rifabutin

•    St. John’s wort

Management

Women on short-term treatment with drugs and herbal products that interact with hormonal contraception and may decrease plasma levels of contraceptive hormones could have their contraceptive effectiveness reduced. They should therefore temporarily use a barrier contraceptive method (e.g. condoms, diaphragm) in addition to Micronor during the time of concomitant medicinal product administration and for 28 days after their discontinuation.

For women on long-term treatment with drugs and herbal products that interact with hormonal contraception, another reliable, non-hormonal method of contraception is recommended.

Physicians are advised to consult the labelling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives and the possible need to adjust dosages.

4.6 Pregnancy and lactation

4.6.1.    Use during pregnancy

Not indicated during pregnancy. Confirm suspected pregnancy before discontinuing treatment.

Many studies have found no effects on foetal development associated with long-term use of contraceptive doses of oral progestogens. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use.

4.6.2.    Use during lactation

In most women, progestogen-only contraceptives, such as Micronor, do not affect the quantity and quality of breast milk or length of lactation. However, isolated postmarketing cases of decreased milk production have been reported. Studies with various orally administered progestogen-only contraceptives have shown that small amounts of progestogens pass into the breast milk of nursing mothers resulting in detectable steroid levels in infant plasma. No adverse effects have been found on the health, growth or development of the infant.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

The safety of Micronor was evaluated in 3099 subjects in 2 clinical trials. Of these, 2925 subjects participated in a clinical trial of Micronor 0.35 mg administered daily, and 174 subjects participated in a clinical trial of Micronor 0.35 mg/day administered on 21 days per cycle. Based on safety data from these clinical trials, the most commonly reported (>5% incidence) adverse drug reactions (ADRs) were (with % incidence): metrorrhagia (34.3%), nausea (8.7%), headache (5.6%), and amenorrhoea (5.4%).

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of Micronor from either clinical trial or post-marketing experiences. The displayed frequency categories use the following convention:

Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

Adverse Drug Reactions

Immune System Disorders
Rare	Hypersensitivity
Frequency not known	Anaphylactic reaction, Anaphylactoid reaction
Psychiatric disorders
Uncommon	Depression, Nervousness
Nervous system disorders
Common	Headache, Dizziness
Gastrointestinal disorders
Common	Vomiting, Nausea
Uncommon	Gastrointestinal disorder. Abdominal pain
Hepatobiliary disorders
Rare	Hepatitis
Frequency not known	Jaundice cholestatic
Skin and subcutaneous tissue disorders
Uncommon	Rash, Acne, Alopecia, Hirsutism
Frequency not known	Rash pruritic
Musculoskeletal and Connective tissue Disorders
Uncommon	Pain in extremity
Pregnancy, Puerperium and Perinatal Conditions
Frequency not known	Ectopic pregnancy
Reproductive system and breast disorders
Very Common	Metrorrhagia
Common	Amenorrhoea, Breast tenderness
Uncommon	Ovarian cyst, Genital discharge, Menorrhagia

Frequency not known	Breast pain, Vaginal haemorrhage, Menstruation irregular, Menstruation delayed, Suppressed lactation, Withdrawal bleed when product is stopped
General disorders and administration site conditions
Common	Fatigue
Uncommon	Oedema
Investigations
Common	Weight increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No serious ill effects have been reported following acute ingestion of large doses of oral contraceptives. Overdosage may cause nausea, vomiting and vaginal bleeding. There are no antidotes and treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Micronor oral contraceptive tablets have a progestational effect on the endometrium and the cervical mucus.

5.2 Pharmacokinetic properties

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

5.3 Preclinical safety data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6.1 List of excipients

Lactose

Magnesium stearate Pregelatinised starch

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

36 months.

6.4 Special precautions for storage

Store at room temperature (below 25 °C). Protect from light.

6.5 Nature and contents of container

PVC/aluminium foil blister strips with or without a card wallet in cardboard carton, containing either 42, 2 x 42, 3 x 28, 1 x 28 or 100 x 28 tablets.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Janssen-Cilag Ltd

50 -100 Holmers Farm Way

High Wycombe

Buckinghamshire