Norethisterone 5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Norethisterone 5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Norethisterone 5.0mg For excipients, see 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
Norethisterone has the following clinical indications:
At low dose:
Metropathia haemorrhagica Pre-menstrual syndrome Postponement of menstruation Dysmenorrhoea Endometriosis Menorrhagia
At high dose:
Disseminated carcinoma of the breast
4.2 Posology and method of administration
For oral administration
Low dose
1. Metropathia haemorrhagica (dysfunctional uterine bleeding): 5mg three times daily for ten days. Bleeding is arrested usually within one to three days. A withdrawal bleeding resembling normal menstruation occurs within two to four days after discontinuing treatment.
Prophylaxis of 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 5mg twice daily from the 19th to the 26th day of the cycle.
2. Pre-menstrual syndrome (including pre-menstrual mastalgia): Pre-menstrual symptoms such as headache, migraine, breast discomfort, water retention, tachycardia and psychic disturbances may be relieved by the administration of 10 - 15mg 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.
3. Postponement of menstruation: In cases of too frequent menstrual bleeding, and in special circumstances (e.g. operations, travel, sports) 5mg three times daily, starting three days before the expected onset of menstruation. A normal period should occur two to three days after the patient has stopped taking tablets.
4. Dysmenorrhoea: Functional or primary dysmenorrhoea is almost invariably relieved by the suppression of ovulation. 5mg three times daily for 20 days, starting on the fifth day of the cycle (the first day of menstruation counting as day one). 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.
5. Endometriosis (pseudo-pregnancy therapy): long-term treatment is commenced on the fifth day of the cycle with 10mg daily for the first few weeks. In the event of spotting, the dosage is increased to 20mg and, if necessary, 25mg daily.
After bleeding has ceased, the initial dose is usually sufficient. Duration of treatment: four to six months continuously, or longer if necessary.
6. Menorrhagia (hypermenorrhoea): 5mg two to three times a day from the 19th to the 26th day of the cycle (counting the first day of menstruation as day one).
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.
Not for use in children.
Not for elderly patients.
4.3 Contraindications
Norethisterone 5mg tablets 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 5mg Tablets, the use of the preparation must be discontinued immediately.
1. Hypersensitivity to the active substance or to any of the excipients.
2. Known or suspected pregnancy.
3. Lactation.
4. Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism).
5. Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).
6. Presence or a history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).
7. A high risk of venous or arterial thrombosis (see section 4.4)
8. History of migraine with focal neurological symptoms.
9. Diabetes mellitus with vascular involvement.
10. Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
11. Previous or existing liver tumours (benign or malignant).
12. Known, past or suspected sex hormone-dependent malignancies, including breast or genital tract carcinoma, unless norethisterone is being used as part of the management of these conditions.
13. History during pregnancy of idiopathic jaundice, severe pruritus or pemphigoid gestationis.
14. Undiagnosed genital bleeding.
15. Untreated endometrial hyperplasia.
16. Active trophoblastic disease (until return to normal of urine- and plasma gonadotrophin concentration) - seek specialist advice. Patients should not use norethisterone after a recent evacuation of a hydatiform mole.
17. Porphyria
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 5mg Tablets, an individual risk-benefit analysis should be done before Norethisterone 5mg Tablets 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:
1. Positive personal or family history (VTE in a sibling or a parent at a relatively early age)
2. Age
3. Obesity
4. Systemic lupus erythematous (SLE)
5. Prolonged immobilisation
6. Major surgery
7. 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 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 5 mg Tablets 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 5 mg Tablets.
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.
Norethisterone should be used in caution in women with a history of ectopic pregnancy.
Progestogens should be used with caution in women with functional ovarian cysts
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
• Other conditions which may be aggravated by fluid retention
If menstrual bleeding should fail to follow a course of Noreththisterone 5 mg Tablets, 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 Tablets is expected to result in similar pharmacological effects as seen with Combined Oral Contraceptives (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 COC 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
Antidepressants: St John’s wort may reduce serum levels of progestogens by enhancing their metabolism.
Anticoagulants: Progestogens may enhance or reduce anticoagulant effect of coumarins and antagonise anticoagulant effect of pheninidione.
Antidiabetics: norethisterone may antagonise the effects of antidiabetics.
Antidepressants: Concomitant use of St. John’s wort with progesterone should be avoided.
Antiepileptics: Hepatic enzyme-inducing antiepileptic drugs, e.g. eslicarbazepine, rufinamide, carbamazepine, oxcarbazepine, phenytoin, topiramate and barbiturates (including phenobarbital and primidone) may enhance the metabolism of progestogens. Norethisterone may reduce lamotrigine plasma concentration.
Antifungals: The effect of norethisterone may be reduced by griseofulvin, possibly by accelerated metabolism of the progestogen.
Antituberculous drugs: Rifamycins may accelerate metabolism of progestogens.
Antiviral drugs: Nevirapine, nelfinavir or ritonavir may accelerate metabolism of norethisterone. Norethisterone plasma concentration increased with concomitant
administration of amprenavir. Amprenavir plasma concentration decreased with concomitant administration of norethisterone.
Dopaminergics: Progestogens increase plasma concentration of selegiline (with an increased risk of toxicity)
Drugs for reversal of neuromuscular blockade: Plasma concentrations of progestogens possibily reduced with the use of sugammadex.
Immunosuppressants: ciclosporin. Metabolism is inhibited by progestogens.
Lipid regulating drugs: Atorvastatin increases plasma concentration of norethisterone.
Muscle relaxants: Progestogens possibly increase plasma concentration of tizanidine (with an increased risk of toxicity)
Vasodilator antihypertensives: Sitaxentan increases plasma concentration of progestogens.
Cytochrome P450 hepatic enzymes are those enzymes of concern, which may be affected by drug interaction resulting in either induction or inhibition of drug metabolism.
4.6 Fertility, pregnancy and lactation
Norethisterone is contraindicated in pregnancy, and should be avoided during lactation, as it is present in breast milk.
Hypospadias in males and virilisation of females has been reported in the offspring of mothers who have taken norethisterone during pregnancy.
4.7 Effects on ability to drive and use machines
None.
4.8 Undesirable effects
Side-effects rarely occur with doses of 15mg daily.
Gastrointestinal disorders: gingival inflammation, nausea, abdominal pain and vomiting,
General: fatigue, drowsiness or insomnia, headache, fever, dizziness
Hepato-biliary disorders: alterations in liver function have been reported and jaundice has been reported rarely.
Immune system disorders: anaphylaxis or anaphylactoid reactions may occur rarely; allergic skin rashes.
Psychiatric disorders: depression and nervousness.
Metabolism and nutrition disorders: hyperglycaemia, changes in appetite or weight gain, oedema and fluid retention, hypercalcaemia, hyperinsulinaemia, and the potential for changes in serum lipid and lipoprotein concentrations to occur with noterthisterone.
Nervous system disorders: exacerbation of epilepsy and migraine.
Ophthalmic disorders: intolerance to contact lenses and deterioration in vision in patients who are short sighted has been reported with the use of the combined oral contraceptive pill and may be applicable to this product.
Reproductive disorders: The commonest side-effect is breakthrough bleeding, particularly when treatment is continuous over a long period. Other menstrual irregularities may occur, including amenorrhoea, spotting and menorrhagia. .Breast changes, including discomfort; ovarian cysts; changes in libido; premenstrual syndrome like symptoms; Androgenic effects with hirsutism and oestrogenic effects have been reported after prolonged therapy. There is a small increase in the risk of having breast cancer diagnosed.
Vascular disorders: Rarely, thromboembolic events with high doses. Hypertension can potentially occur with norethisterone.
Skin and subcutaneous tissue disorders: acne, alopecia, allergic skin rashes, urticaria, pruritus, and melasma or chloasma.
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
There are no reports of ill-effects from overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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.
5.2 Pharmacokinetic properties
Norethisterone is absorbed from the gastro-intestinal tract and its effects last for at least 24 hours. It is excreted in the urine.
• Metabolism
Norethisterone is partly metabolised 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.
5.3 Preclinical safety data
There are no pre-clinical data of any relevance to the prescriber which are additional to those already included in other sections.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose Starch Maize Magnesium Stearate
6.2 Incompatibilities
None.
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.
6.6 Special precautions for disposal
None.
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF U.K.
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0152
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/03/2009
10 DATE OF REVISION OF THE TEXT
11/09/2015