SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Norethisterone Tablets BP 5mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 5mg of Norethisterone.

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

1.    Metropathia haemorrhagica.

2.    Premenstrual syndrome.

3.    Postponement of menstruation.

4.    Dysmenorrhoea.

5.    Endometriosis.

6.    Menorrhagia.

7.    Disseminated Carcinoma of the breast.

4.2    Posology and method of administration

Posology

Metropathia haemorrhagica (dysfunctional uterine bleeding): 1 tablet 3 times daily for 10 days. Bleeding is arrested usually within 1-3 days. A withdrawal bleeding resembling normal menstruation occurs within 2-4 days after discontinuing treatment.

Prophylaxis against recurrence of dysfunctional bleeding: If there are no signs of resumption of normal ovarian function (no rise of morning temperature in the second half of the cycle), recurrence must be anticipated. Cyclical bleeding can be established with 1 tablet twice daily from the 19th to the 26th day of the cycle.

Premenstrual syndrome (including premenstrual mastalgia): Premenstrual symptoms such as headache, migraine, breast discomfort, water retention, tachycardia and psychic disturbances may be relieved by the administration of 2-3 tablets daily from the 19th to the 26th day of the cycle. Treatment should be repeated for several cycles. When treatment is stopped, the patient may remain symptom-free for a number of months.

Postponement of menstruation: In cases of too frequent menstrual bleeding, and in special circumstances (eg operations, travel, sports) Dosage: 1 tablet three times daily, starting 3 days before the expected onset of menstruation. A normal period should occur 2-3 days after the patient has stopped taking tablets.

Dysmenorrhoea: functional or primary dysmenorrhoea is almost invariably relieved by the suppression of ovulation. 1 tablet three times daily for 20 days, starting on the fifth day of the cycle (the first day of menstruation counting as day 1). Treatment should be maintained for three to four cycles followed by treatment-free cycles. A further course of therapy may be employed if symptoms return.

Endometriosis (pseudo-pregnancy therapy): long-term treatment is commenced on the 5th day of the cycle with 2 tablets daily for the first few weeks. In the event of spotting, the dosage is increased to 4 and, if necessary, 5 tablets daily.

After bleeding has ceased, the initial dose is usually sufficient. Duration of treatment: 4-6 months continuously, or longer if necessary.

Menorrhagia (hypermenorrhoea): 1 tablet 2-3 times a day from the 19th to the 26th day of the cycle (counting the first day of menstruation as day 1).

Disseminated Carcinoma: of the breast the starting dose is 8 tablets per day increasing to 12 tablets after 6 weeks if no regression is noted and may be continued indefinitely. If no remission is obtained within 9 weeks of treatment none should be expected.

Not intended for use in children.

Not intended for elderly patients.

Method of Administration For oral use.

4.3 Contraindications

Norethisterone should not be used in the presence of any of the conditions listed below. Should any of the conditions appear during the use of Norethisterone, the use of the preparation must be discontinued immediately.

•    Hypersensitivity to the active substance or to any of the excipients.

•    Known or suspected pregnancy.

•    Lactation.

•    Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism).

•    Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).

•    Presence or a history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).

•    A high risk of venous or arterial thrombosis (see section 4.4)

•    History of migraine with focal neurological symptoms.

•    Diabetes mellitus with vascular involvement.

•    Presence or history of severe hepatic disease as long as liver function values have not returned to normal.

•    Previous or existing liver tumours (benign or malignant).

•    Known, past or suspected sex hormone-dependent malignancies, including breast cancer.

•    History during pregnancy of idiopathic jaundice or severe pruritus.

•    Undiagnosed genital bleeding.

•    Untreated endometrial hyperplasia.

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

4.4 Special warnings and precautions for use

Medical Examination

A complete personal and family medical history should be taken for 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 which should be adapted to the individual woman and should include measurement of blood pressure, and if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.

Therapy should be discontinued immediately if the following occur:

•    New onset of migraine-type headaches or more frequent occurrence of unusually severe headaches

•    Sudden perceptual disorders (e.g. disturbances of vision or hearing)

•    First signs of thrombophlebitis or thromboembolic symptoms, feeling of pain and tightness in the chest

•    Pending operations (six weeks beforehand), immobilisation (e.g. after accidents)

•    Onset of jaundice or deterioration in liver function, anicteric hepatitis, general pruritus

•    Significant increase in blood pressure

•    Pregnancy.

If any of the conditions/risk factors mentioned below is present or deteriorates while using Norethisterone, an individual risk-benefit analysis should be done before Norethisterone is started or continued.

•    Circulatory disorders

It has been concluded from epidemiological surveys that the use of oral oestrogen/progestogen containing ovulation inhibitors is associated by an increased incidence of thromboembolic diseases. Therefore, one should keep the possibility of an increased thromboembolic risk in mind, particularly where there is a history of thromboembolic diseases.

A patient who develops symptoms suggestive of thromboembolic complications should stop treatment immediately. The need for treatment should be reassessed before continuing therapy.

Generally recognised risk factors for venous thromboembolism (VTE) include:

•    Positive personal or family history (VTE in a sibling or a parent at a relatively early age)

•    Age

•    Obesity

•    Systemic lupus erythematous (SLE)

•    Prolonged immobilisation

•    Major surgery

•    Major trauma.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. The treatment with steroid hormone may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thromboembolic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of progestogens in these patients should be viewed as contraindicated. Where a patient is already taking anticoagulants, the risk and benefits of progestogen therapy should be carefully considered.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients, scrupulous attention should be given to prophylactic measures to prevent VTE. Where prolonged immobilisation is likely to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to stopping progestogen therapy 4-6 weeks pre-operatively. Treatment should not be restarted until the patient is fully remobilised.

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

•    Known Hyperlipidaemias

Women with hypertriglyceridemia, or a family history thereof, may be at increased risk of pancreatitis when using COCs.

Women with hyperlipiaedmia are at increased risk of arterial disease (see section 4.4 “Circulatory disorders”). However, routine screening of women on COCs is not appropriate.

•    Tumours

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of hormonal substances such as the one contained in Norethisterone. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis and, if necessary, the preparation should be withdrawn.

•    Other

Norethisterone can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation when taking Norethisterone.

Patients who have a history of depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

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

Any patient who develops an acute impairment of vision, proptosis, diplopia or migraine headache should be carefully evaluated ophthalmologically to exclude papilloedema or retinal lesions before continuing medication.

Progestogens may cause fluid retention. Special care should be taken when prescribing norethisterone in patients with conditions which might be aggravated by this factor:

•    Epilepsy

•    Migraine

•    Asthma

•    Cardiac dysfunction

•    Renal dysfunction.

If menstrual bleeding should fail to follow a course of Norethisterone, or if the patient wishes to postpone menstruation in special circumstances, the possibility of pregnancy must be excluded before a further course is given.

Additional warnings based on the partial metabolisation of norethisterone to ethinylestradiol

After oral administration, norethisterone is partly metabolised to ethinylestradiol resulting in an equivalent dose of about 4-6 micrograms ethinylestradiol per 1 milligram of orally administered norethisterone or norethisterone acetate (see section 5.2)

Due to the partial conversion of norethisterone to ethinylestradiol, administration of Norethisterone is expected to result in similar pharmacological effects as seen with COCs. Therefore, the following general warnings associated with the use of COCs should also be considered:

•    Circulatory disorders (thromboembolic events)

Venous thromboembolic events (VTE)

Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in users of oral contraceptives with low oestrogen content (<50 pg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users. The use of any combined oral contraceptive carries an increased risk of VTE compared with no use. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies. The excess risk of VTE is highest during the first year a woman initially starts using a COC or when she restarts COC use after a pill-free interval of at least a month.

VTE may be life-threatening or may have a fatal outcome (in 1-2 % of the cases).

VTE manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs.

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Common signs/symptoms of VTE include:

•    Severe pain in the calf of one leg; swelling of the lower leg

•    Sudden breathlessness, chest pain.

Arterial thromboembolic related conditions

The use of a combined oral contraceptive may also increase the risk of conditions such as stroke and myocardial infarction which are secondary to arterial thromboembolic events.

Common signs/symptoms associated with arterial thromboembolism include:

•    sudden severe pain in the chest, whether or not reaching to the left arm;

•    sudden coughing for no apparent reason

•    any 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;

-    collapse with or without focal epilepsy;

-    weakness or very marked numbness suddenly affecting one side or one part of the body.

Risk Factors for Thromboembolic Events:

•    Age

•    Obesity (body mass index over 30 kg/m2)

•    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 known or suspected, the woman should be referred to a specialist for advice before deciding about any COC use

•    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 four weeks in advance) and not to resume until two weeks after complete remobilisation

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

•    Dyslipoproteinaemia

•    Hypertension

•    Migraine (An increase in frequency or severity of migraine during COC use may be prodromal of a cerebrovascular event and therefore a reason for immediate discontinuation of the COC).

•    Valvular heart disease

•    Atrial fibrillation

Other _ factors affecting circulatory events

Other medical conditions which have been associated with adverse circulatory events include:

•    Diabetes mellitus

•    Systemic lupus erythematosus (SLE)

•    Haemolytic uremic syndrome

•    Chronic inflammatory bowel disease (Crohn's disease/Ulcerative colitis)

•    Sickle cell disease.

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 (<0.05 mg ethinylestradiol).

•    Tumours

Cervical Cancer

The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may

further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

Breast Cancer

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 COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of 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. These studies do not provide evidence for causation. 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 breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

Malignancies may be life-threatening or may have a fatal outcome.

•    Other

Blood pressure

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy. Conditions which deteriorate in _pregnancy or during_previous COC use The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive:

•    jaundice and/or pruritus related to cholestasis

•    gallstone formation

•    porphyria

•    systemic lupus erythematosus (SLE)

•    haemolytic uremic syndrome

•    Sydenham's chorea

•    herpes gestationis

•    otosclerosis-related hearing loss.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Crohn's disease and ulcerative colitis have been associated with COC use.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of Norethisterone will be altered if other sex hormones are prescribed simultaneously.

The metabolism of progestogens may be increased by concomitant administration of compounds known to induce drug-metabolising enzymes, especially cytochrome. P450 enzymes. These compounds include anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz, tetracyclines, ampicillin, oxacillin and co-trimoxazole)

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibits inducing propoerties when used concomitantly with steroid hormones.

Herbal preparations containing St John’s Wort (Hypericum Perforatum) may induce the metabolism of progestogens, therefore progestogen levels may be reduced.

Aminoglutethimide has been reported to decrease plasma of levels of some progestogens.

Concurrent administration of ciclosporin and norethisterone has been reported to lead to increased plasma ciclosporin and/or decrease plasma norethisterone levels.

Care should be taken when progestogens are administered with other medicines which also cause fluid retention, for example NSAIDs and vasodilators.

Other forms of interactions:

Progestogens can influence certain laboratory tests (e.g. tests for hepatic function, thyroid function, coagulation, dextrose, cortisol, gonadotropin, testosterone, progesterone and oestrogen).

4.6 Pregnancy and lactation

Norethisterone is contraindicated in pregnancy, and should be avoided during lactation as it is present in breast milk.

4.7 Effects on ability to drive and use machines

Patients should be cautioned about the possibility of dizziness, drowsiness and visual changes and informed of its significance in the driving of vehicles and the operation of machinery.

4.8 Undesirable effects

Side effects rarely occur in doses of 15mg daily.

Progestogens given alone at low doses have been associated with the following undesirable effects:

Genitourinary: breakthrough bleeding , spotting, amenorrhoea, abnormal bleeding (irregular, increase or decrease), alterations of cervical secretions, cervical erosions, prolonged anovulation.

Breast galactorrhoea, mastodynia, tenderness.

Gastrointestinal: nausea, vomiting.

Cardiovascular: thrombo-embolic disorders, increased blood pressure, pulmonary embolism, retinal thrombosis, thrombophlebitis.

Hepatobiliary: cholestatic liver changes, disturbed liver function.

Neurological and Special Senses: depression, headache, dizziness, fatigue, insomnia, nervousness, drowsiness, loss of concentration, vision disorders and intolerance to contact lenses.

Metabolic and Nutritional: altered serum lipid and lipoprotein profiles, incresed fasting insulin levels, decreased glucose tolerance, diabetic cataract, exacerbation of diabetes mellitus, glyosuria.

Skin and Mucous membranes: acne, hirsutism, alopecia, rash, uticaria, exacerbation of existing skin conditions.

Hypersensitivity reactions: (e.g. anaphylaxis and anaphylactoid reactions, angioedema).

Miscellaneous: oedema, fluid retention, bloating, weight gain, fever, change in appetite, deepening of the voice, change in libido.

4.9 Overdose

Overdosage may present as nausea, vomiting, breast enlargement and later vaginal bleeding. There is no specific antidote and treatment should be symptomatic.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC code: G03DC02

Norethisterone is a synthetic, potent, orally-active progestogen which, by virtue of its progestogenic effects, produces secretory effects on oestrogen-primed genital tissue, has a sedative effect on uterine muscle and a styptic effect on uterine haemorrhage.

Norethisterone also has some androgenic effects and some weak oestrogenic activity.

In carcinoma norethisterone may act by pituitary inhibition by an anti oestrogenic effect or by direct action on the tumour. The mode of action is not fully understood.

5.2 Pharmacokinetic properties

Norethisterone when given orally is well absorbed from the gastrointestinal tract, with peak plasma concentrations (which may be dose-dependent) generally occurring within 1-2^ hours and its effects last for at least 24 hours.

Bioavailability of Norethisterone is variable, probably due to first-pass effects in gut-wall or liver, which may be influenced by many factors including hormonal status, diet and exercise.

Metabolism

Norethisterone is partly metabolized to ethinylestradiol after oral administration of

norethisterone or norethisterone acetate in humans. This conversion results in an

equivalent dose of about 4-6 pg ethinylestradiol per 1 mg orally administered norethisterone / norethisterone acetate.

Plasma half-life after a dose of 5mg is of the order of 5 hours. After 24 hours plasma levels are generally about 1% of peak concentration. Approximately 60% of the administered dose is excreted as metabolites in the urine and faeces.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The tablets also contain:

Lactose Maize starch Magnesium stearate

6.2 Incompatibilities

None known

6.3 Shelf life

Shelf-life 60 Months.

Shelf-life after dilution/reconstitution Not applicable.

Shelf-life after first opening

Not applicable.

6.4    Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5    Nature and contents of container

1.    Opaque plastic containers with press-on tamper-evident lid.

2.    Blister pack of PVC and aluminium foil.

Pack sizes: 100’s, 500’s (Opaque plastic container)

Pack sizes: 30’s, 72’s, 180’s (Blister pack)

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley Barnstaple North Devon EX32 8NS

8    MARKETING AUTHORISATION NUMBER

PL 00142/0483

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/08/1999 / 29/03/2005

10 DATE OF REVISION OF THE TEXT

05/07/2016