This information is intended for use by health professionals

1. Name of the medicinal product

Norethisterone 5mg Tablets

2. Qualitative and quantitative composition

Norethisterone 5.0mg.

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Tablet.

Norethisterone 5mg Tablets are 6.5mm, round, white, uncoated tablets with “NE 5” on one side and a break line on the other.

4. Clinical particulars
4.1 Therapeutic indications

At low dose:

Dysfuntional uterine bleeding

Polymenorrhoea

Menorrhagia

Metropathia

Haemorrhagia

Pre-menstrual syndrome

Postponement of menstruation

At high dose:

Disseminated carcinoma of the breast.

4.2 Posology and method of administration

Posology

Low dose

Dysfunctional uterine bleeding, polymenorrhoea, menorrhagia, dysmenorrhoea and metropathia haemorrhagia: 1 tablet three times daily for 10 days; bleeding usually stops within 48 hours. Withdrawal bleeding resembling true menstruation occurs a few days after the end of treatment. One tablet twice daily, from days 19 to 26 of the two subsequent cycles, should be given to prevent recurrence of the condition.

Endometriosis: 1 tablet three times daily for a minimum treatment period of six months. The dosage should be increased to 4 or 5 tablets a day if spotting occurs. The initial dosage should be resumed when bleeding or spotting stops.

Postponement of menstruation: 1 tablet three times daily, starting three days before the expected onset of menstruation. Menstruation usually follows within three days of finishing the treatment.

Pre-menstrual syndrome: 1 tablet daily from days 16 to 25 of the menstrual cycle.

High dose

For disseminated breast carcinoma the starting dose is 8 tablets (40mg) per day increasing to 12 tablets (60mg) if no regression is noted.

Method of administration

Oral Administration

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1

Pregnancy

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

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

Disturbance of liver function

History during pregnancy of idiopathic jaundice

Severe pruritus or pemphigoid gestationis

Undiagnosed irregular vaginal bleeding

Porphyria

4.4 Special warnings and precautions for use

If menstrual bleeding should fail to follow a course of Utovlan, the possibility of pregnancy must be excluded before a further course is given.

Therapy should be discontinued if the following occur:

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

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

Risk of venous thromboembolism (VTE)

Long term use of low dose progestogens as part of combined oral contraception or combined hormone replacement therapy has been associated with an increased risk of venous thromboembolism, although the role of progestogens in this aetiology is uncertain. A patient who develops symptoms suggestive of thromboembolic complications should have her status and need for treatment carefully assessed before continuing therapy.

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

Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI >30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Treatment with steroid hormones may add to these risk factors. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophillic predisposition. Until a thorough evaluation of thrombophillic 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 risks 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.

If VTE develops after initiating therapy the drug should be withdrawn. Patients should be advised to contact their doctor immediately if they become aware of a potential thromboembolic symptom (e.g., painful swelling in the leg, sudden pain in the chest, dyspnoea).

4.5 Interaction with other medicinal products and other forms of interaction

Interaction with other medicines

The metabolism of progestogens may be increased by concomitant administration of compounds known to induce drug-metabolising enzymes, specifically 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 cotrimoxazole)

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of progestogens. Progestogen levels may therefore be reduced.

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

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

When used in combination with cytotoxic drugs, it is possible that progestogens may reduce the haematological toxicity of chemotherapy.

Special care should be taken when progestogens are administered with other drugs which also cause fluid retention, such as NSAIDs and vasodilators.

Other forms of interaction

Progestogens can influence certain laboratory tests (e.g., tests for hepatic function, thyroid function and coagulation).

4.6 Fertility, pregnancy and lactation

Norethisterone is contraindicated in pregnancy

4.7 Effects on ability to drive and use machines

Norethisterone has no influence on the ability to drive and use machines.

4.8 Undesirable effects

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

Genitourinary

breakthrough bleeding, spotting, amenorrhoea, abnormal uterine bleeding, (irregular, increase, decrease), alterations of cervical secretions, cervical erosions, prolonged anovulation

Breast

galactorrhoea, mastodynia, tenderness

Central Nervous System

depression, headache, dizziness, fatigue, insomnia, nervousness, somnolence, confusion, euphoria, loss of concentration, vision disorders

Gastrointestinal/Hepatobiliary

nausea, vomiting, cholestatic icterus/jaundice, constipation, diarrhoea, dry mouth, disturbed liver function

Metabolic & Nutritional

altered serum lipid and lipoprotein profiles, increased fasting glucose levels, increased fasting insulin levels, decreased glucose tolerance, adrenergic-like effects (e.g., fine hand tremors, sweating, cramps in calves at night), corticoid-like effects (e.g., Cushingoid syndrome), diabetic cataract, exacerbation of diabetes mellitus, glycosuria

Cardiovascular

thrombo-embolic disorders, cerebral and myocardial infarction, congestive heart failure, increased blood pressure, palpitations, pulmonary embolism, retinal thrombosis, tachycardia, thrombophlebitis

Skin & Mucous Membranes

acne, hirsutism, alopecia, pruritis, rash, urticaria

Allergy

hypersensitivity reactions (e.g., anaphylaxis & anaphylactoid reactions, angioedema)

Miscellaneous

oedema/fluid retention, bloating, weight gain, pyrexia, change in appetite, change in libido, hypercalcaemia, malaise

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

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

Gastric lavage may be employed if the overdosage is large and the patient is seen sufficiently early (within four hours).

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmotherapeutic group (ATC code) L02A B.

Norethisterone given at intermediate doses (5-10mg) suppresses ovulation via its effect on the pituitary. The endogenous production of oestrogens and progesterones are also suppressed, and the ectopic endometrium is converted to a decidua resembling that of pregnancy. In carcinoma norethisterone may act by pituitary inhibition or by direct action on tumour deposits.

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5.2 Pharmacokinetic properties

Norethisterone is rapidly and completely absorbed after oral administration, peak plasma concentration 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.

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.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose

Maize starch

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Five years.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5 Nature and contents of container

Opaque plastic tablet containers with press-on tamper evident lid containing 100 and 500 tablets.

Blister pack of PVC and aluminium foil containing 30, 72 and 180 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing authorisation number(s)

PL 29831/0152

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 04 August 1999

Date of latest renewal: 02 March 2009

10. Date of revision of the text

13 February 2017