1. Name Of The Medicinal Product
Trisequens®
Trisequens® Forte
2. Qualitative And Quantitative Composition
Trisequens
28 sequential tablets: 12 blue, 10 white, 6 red.
Active ingredients:
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Trisequens Forte
28 sequential tablets: 12 yellow, 10 white, 6 red.
Active ingredients:
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3. Pharmaceutical Form
Film-coated tablets for oral administration.
4. Clinical Particulars
4.1 Therapeutic Indications
a) The treatment of symptoms due to oestrogen deficiency.
b) Second line therapy for prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis (Trisequens only).
4.2 Posology And Method Of Administration
4.2.1 Dosage: Adults: Menopausal symptoms and prophylaxis of osteoporosis.
Trisequens and Trisequens Forte are administered orally, without chewing, one tablet daily without interruption, starting with the blue or yellow tablets respectively.
For menopausal symptoms treatment should be instituted with Trisequens. If the clinical response is unsatisfactory, Trisequens Forte may be tried. Treatment with Trisequens Forte should be replaced by Trisequens as soon as symptoms can be relieved with the lower dose.
Prophylaxis of osteoporosis: Hormone replacement therapy (HRT) has been found to be effective in the prevention of osteoporosis, especially when started soon after the menopause and used for 5 years and probably up to 10 years or more. Treatment should ideally start as soon as possible after the onset of the menopause and certainly within 2 to 3 years. Protection appears to be effective for as long as treatment is continued. However, data beyond 10 years are limited. A careful re-appraisal of the risk-benefit ratio should be undertaken before treating for longer than 5 to 10 years.
Use in the elderly: There are no special dosage requirements.
Not intended for children or males.
4.2.2 Administration: In menstruating women the first tablet should be taken on the fifth day of menstrual bleeding. If menstruation has stopped altogether or is infrequent and sporadic (2-4 monthly intervals) the first tablet can be taken at any time.
A regular shedding of the endometrium is usually induced during the red tablet phase or at the end of the white tablet phase.
Before initiation of therapy it is recommended that the patient is fully informed of all likely benefits and potential risks.
Since progestogens are only administered to protect against hyperplastic changes of the endometrium, patients without a uterus should be treated with an oestrogen-only preparation.
4.3 Contraindications
1 Known, suspected or past history of cancer of the breast.
2 Known or suspected oestrogen-dependent neoplasia.
3 Undiagnosed irregular vaginal bleeding.
4 Known or suspected pregnancy.
5 Active deep venous thrombosis, thromboembolic disorders or a history of confirmed venous thromboembolism.
6 Active or chronic liver disease or history of liver disease where the liver function tests have failed to return to normal.
7 Rotor's syndrome or Dubin-Johnson syndrome.
8 Severe cardiac or renal disease.
9 Hypersensitivity to one or more of the constituents.
4.4 Special Warnings And Precautions For Use
1 Assessment of each woman prior to taking hormone replacement therapy (and at regular intervals thereafter) should include a personal and family medical history. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for the product. During assessment of each individual women clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national breast cancer screening programme (mammography) and the national cervical cancer screening programme (cervical cytology) as appropriate for their age. Breast awareness should also be encouraged and women advised to report any changes in their breasts to the doctor or nurse.
2 Endometrial assessment should be carried out if indicated; this may be particularly relevant in patients who are, or who have been, treated with oestrogen unopposed by a progestagen.
In the female there is an increased risk of endometrial hyperplasia and carcinoma associated with unopposed oestrogen administered long term (for more than one year). However, the appropriate addition of a progestogen to an oestrogen regimen lowers this additional risk.
3 If abnormal or irregular vaginal bleeding occurs during or shortly after therapy, diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out the possibility of uterine malignancy.
4 A reanalysis of original data from 51 epidemiological studies reported a small or moderate increase in the probability of having breast cancer diagnosed in women currently or recently using HRT. The findings may be due to biological effects of HRT, earlier diagnosis, or a combination of both. The relative risk increased with duration of treatment (by 2.3% per year of use) and returned to normal in the course of five years after cessation of HRT use. This is comparable to the increase in relative risk when natural menopause is delayed in the absence of HRT. Breast cancers diagnosed in current or recent users of HRT are more likely to be localised to the breast than those found in non-users. HRT use may not be associated with increased mortality from breast cancer.
Between the ages of 50 and 70, about 45 women in every 1000 not using HRT will have breast cancer diagnosed. It is estimated that among those who use HRT for 5 years starting at age 50, 2 extra cases of breast cancer will be detected by age 70 in every 1000 women. For those who use HRT for 10 years there will be 6 extra cases of breast cancer, and for 15 years use, 12 extra cases of breast cancer in every 1000 women during the 20 year period until age 70.
It is important that the increased risk of being diagnosed with breast cancer is discussed with the patient and weighed against the known benefits of HRT.
5 Certain diseases may be made worse by hormone replacement therapy and patients with these conditions should be closely monitored. These include otosclerosis, multiple sclerosis, systemic lupus erythematosus, porphyria, melanoma, epilepsy, migraine and asthma. In addition, pre-existing uterine fibroids may increase in size during oestrogen therapy and symptoms associated with endometriosis may be exacerbated.
6 Epidemiological studies have suggested that hormone replacement therapy (HRT) is associated with a higher relative risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. The studies find a 2-3 fold higher risk for users compared with non-users which for healthy women amounts to one extra case of VTE each year for every 5000 patients taking HRT.
Generally recognised risk factors for VTE include a personal history or family history and severe obesity (Body Mass Index >30 kg/m2). In women with these factors the benefits of treatment with HRT need to be carefully weighed against the risks. There is no consensus about the possible role of varicose veins in VTE.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. In women on HRT scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is likely to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 weeks earlier, if possible.
If venous thromboembolism develops after initiating therapy the drug should be discontinued.
7 Oestrogens may cause fluid retention and, therefore, patients with cardiac or renal dysfunction should be carefully observed.
8 If jaundice, migraine-like headaches, visual disturbance or a significant increase in blood pressure develop after initiating therapy, the medication should be discontinued while the cause is investigated.
9 Trisequens and Trisequens Forte are not contraceptives, neither will they restore fertility.
10 Most studies indicate that oestrogen replacement therapy has little effect on blood pressure and some indicate that oestrogen use may be associated with a small decrease in B.P. In addition, most studies on combined therapy, including Trisequens and Trisequens Forte, indicate that the addition of a progestogen also has little effect on blood pressure. Rarely, idiosyncratic hypertension may occur.
However, when oestrogens are administered to hypertensive women, supervision is necessary and blood pressure should be monitored at regular intervals.
11 Diabetic patients should be carefully observed when initiating hormone replacement therapy, as worsening glucose tolerance may occur.
12 Changed oestrogen levels may affect certain endocrine and liver function tests.
13 It has been reported that there is an increase in the risk of surgically confirmed gall bladder disease in women receiving postmenopausal oestrogens.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
May potentiate side effects of phenothiazines. Drugs such as barbiturates, phenytoin and rifampicin, which induce the activity of hepatic microsomal drug metabolising enzymes, may decrease the effectiveness of Trisequens and Trisequens Forte. Mineral oil may decrease the intestinal absorption of Trisequens and Trisequens Forte.
4.6 Pregnancy And Lactation
Trisequens and Trisequens Forte are contra-indicated during pregnancy and lactation.
4.7 Effects On Ability To Drive And Use Machines
No effects known.
4.8 Undesirable Effects
The following side effects have been reported with oestrogen/progestogen therapy:
1 Genitourinary system: irregular vaginal bleeding, pre-menstrual-like syndrome, increase in size of uterine fibromyomata.
2 Breasts - tenderness, enlargement, secretion.
3 Gastrointestinal - nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice.
4 Skin - chloasma or melasma which may persist when drug is discontinued, erythema multiforme, erythema nodosum, haemorrhagic eruption, loss of scalp hair, hirsutism.
5 Eyes - steepening of corneal curvature, intolerance to contact lenses.
6 CNS - headaches, migraine, dizziness, mental depression, chorea.
7 Miscellaneous - increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, oedema, change in libido, leg cramps.
4.9 Overdose
Overdosage may be manifested by nausea and vomiting. There is no specific antidote and treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
The oestrogen component of Trisequens and Trisequens Forte substitutes for the loss of endogenous oestrogen production which occurs in women around the time of the menopause, whilst the progestogen component counteracts hyperstimulation of the endometrium. A regular shedding of the endometrium is usually induced during the red tablet phase or at the end of the white tablet phase.
Studies based on measurement of bone mineral content have shown that Trisequens is effective in the prevention of progressive bone loss following the menopause.
During treatment with Trisequens total cholesterol and LDL-C are lowered significantly whereas HDL-C and triglycerides are unchanged.
5.2 Pharmacokinetic Properties
The micronised 17β-estradiol in Trisequens and Trisequens Forte is absorbed rapidly and efficiently from the gastrointestinal tract, reaching a peak plasma concentration in 2-4 hours. Following administration of Trisequens, the steady state plasma level of estradiol ranges from between 70-100 pg/ml. Estradiol has a half life of approximately 14-16 hours. In the blood stream more than 90% of estradiol is bound to plasma proteins. Estradiol is oxidized to oestrone, which is converted to oestriol. Both transformations take place mainly in the liver. Oestrogens are excreted into the bile and then undergo reabsorption from the intestine. During this enterohepatic circulation, degradation occurs. Estradiol and its metabolites are excreted either in the urine (90-95%) as biologically inactive glucuronide and sulphate conjugates or in the faeces (5-10%) mostly unconjugated.
Norethisterone acetate is rapidly absorbed and transformed to norethisterone, then metabolised and excreted as glucuronide and sulphate conjugates. About half the dose is recovered in the urine within 24 hours, the remainder being reduced to less than 1% of the dose within 5-6 days. The mean plasma half life is 3-6 hours.
6. Pharmaceutical Particulars
6.1 List Of Excipients
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6.2 Incompatibilities
None known.
6.3 Shelf Life
48 months.
6.4 Special Precautions For Storage
Store in a dry place, protected from light. Store below 25°C. Do not refrigerate.
6.5 Nature And Contents Of Container
Polypropylene/polystyrene calendar dial pack containing 28 tablets. Calendar dial packs (3 x 28 tablets) are contained within outer carton.
6.6 Special Precautions For Disposal And Other Handling
Each carton contains a patient information leaflet with instructions for use of the calendar dial pack.
7. Marketing Authorisation Holder
Novo Nordisk Limited
Broadfield Park, Brighton Road
Crawley, West Sussex, RH11 9RT
8. Marketing Authorisation Number(S)
Trisequens: PL 3132/0122.
Trisequens Forte: PL 3132/0123
9. Date Of First Authorisation/Renewal Of The Authorisation
29 January 1998.
10. Date Of Revision Of The Text
February 1998, August 1999, April 2001, April 2002, Decmeber 2003
LEGAL CATEGORY
Prescription-only medicine (POM).
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