FemTab Sequi

- Each white sugar-coated tablet contains:

Estradiol valerate 2.0mg

- Each pink sugar-coated tablet contains:

Estradiol valerate 2.0mg

Levonorgestrel 75 micrograms

Sugar coated tablets for oral use.

Hormone replacement therapy for the treatment of the climacteric syndrome.

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.

For maximum prophylactic benefit treatment should commence as soon as possible after the menopause.

Bone mineral density measurements may help to confirm the presence of low bone mass.

FemTab Sequi is designed to provide hormone replacement therapy during and after the climacteric. The addition of a progestogen in the second half of each course helps to provide good control of the irregular cycles that are characteristic of the premenopausal phase and opposes the production of endometrial hyperplasia. Whilst ovarian hormone production is little affected, FemTab Sequi abolishes or improves the characteristic symptoms of the climacteric such as hot flushes, sweating attacks and sleep disorders.

Studies of bone mineral content have shown FemTab Sequi to be effective in the prevention of progressive bone loss following the menopause.

FemTab Sequi does not consistently inhibit ovulation and is therefore unsuitable for contraception.

Adults, including the elderly:

If the patient is still menstruating, treatment should begin on the 5th day of menstruation. Patients whose periods are very infrequent or who are postmenopausal may start at any time, provided pregnancy has been excluded (see Section 4.4. Special warnings and special precautions for use).

One white tablet is taken daily for the first 16 days, followed by one pink tablet daily for 12 days. Thus, each pack contains 28 days treatment. Treatment is continuous, which means that the next pack follows immediately without a break. Bleeding usually occurs within the last few days of one pack and the first week of the next.

- Pregnancy (See Section 4.4. Special warnings and special precautions for use)

- severe disturbances of liver function

- previous or existing liver tumours

- jaundice or general pruritus during a previous pregnancy

- Dubin-Johnson syndrome

- Rotor syndrome

- active deep venous thrombosis, thromboembolic disorders, or a history of confirmed venous thromboembolism. (See also Special warnings and special precautions for use).

- sickle-cell anaemia

- suspected or existing hormone-dependent disorders or tumours of the uterus and breast

- undiagnosed irregular vaginal bleeding

- congenital disturbances of lipid metabolism

- a history of herpes gestationis

- otosclerosis with deterioration in previous pregnancies

- endometriosis

- severe diabetes with vascular changes

- mastopathy.

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 FemTab Sequi. During assessment of each individual woman 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 their doctor or nurse.

Before starting treatment, pregnancy must be excluded. If the expected bleeding fails to occur at about 28-day intervals, treatment should be stopped until pregnancy has been ruled out.

Persistent breakthrough bleeding during treatment is an indication for endometrial assessment which may include biopsy.

Epidemiological studies have suggested that hormone replacement therapy (HRT) is associated with an increased relative risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. The studies find a 2-3 fold increase for users compared with non-users which for healthy women amounts to a low risk of one extra case of VTE each year for every 5000 patients taking HRT.

Generally recognised risk factors for VTE include a personal 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 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 liable 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 this is possible.

If venous thromboembolism develops after initiating HRT the drug should be discontinued.

Prolonged exposure to unopposed oestrogens increases the risk of development of endometrial carcinoma. The general consensus of opinion is that the addition of 12 days progestogen towards the end of the cycle, as in FemTab Sequi, diminishes the possibility of such a risk, and some investigators consider that it might be protective.

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 increase in relative risk associated with duration of HRT use is comparable to the increase in relative risk when natural menopause is delayed in the absence of HRT (2.8% increase for each year older at menopause). 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.

Treatment should be stopped at once if migrainous or frequent and unusually severe headaches occur for the first time, or if there are other symptoms that are possible prodromata of vascular occlusion.

Treatment should be stopped at once if jaundice or pregnancy occurs, if there is a significant rise in blood pressure, or an increase in epileptic seizures.

Some women are predisposed to cholestasis during steroid therapy. Diseases that are known to be subject to deterioration during pregnancy (e.g. multiple sclerosis, epilepsy, diabetes, benign breast disease, hypertension, cardiac or renal dysfunction, asthma, porphyria, tetany and otosclerosis) and women with a strong family history of breast cancer should be carefully observed during treatment.

Pre-existing fibroids may increase in size under the influence of oestrogens. If this is observed treatment should be discontinued.

In patients with mild chronic liver disease, liver function should be checked every 8 - 12 weeks.

In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in FemTab Sequi. If severe upper abdominal complaints, enlarged liver, or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnostic considerations.

Hormonal contraception should be stopped when treatment with FemTab Sequi is started and the patient should be advised to take non-hormonal contraceptive precautions.

Drugs which induce hepatic microsomal enzyme systems e.g. barbiturates, phenytoin, rifampicin, accelerate the metabolism of oestrogen/progestogen combinations such as FemTab Sequi and may reduce their efficacy.

The requirement for oral antidiabetics or insulin can change.

Contra-indicated.

None known.

During the first few months of treatment, breakthrough bleeding, spotting and breast tenderness or enlargement can occur. These are usually temporary and normally disappear after continued treatment. Other symptoms known to occur are: anxiety; increased appetite; bloating; palpitations; depressive symptoms; headache; migraine; dizziness; dyspepsia; leg pains; oedema; altered libido; nausea; rashes; vomiting; altered weight; chloasma.

There have been no reports of ill-effects from overdosage, which it is, therefore, generally unnecessary to treat. There are no specific antidotes, and treatment should be symptomatic.

FemTab Sequi contains estradiol valerate (the valeric acid ester of the endogenous female oestrogen, estradiol) and the synthetic progestogen, levonorgestrel. Estradiol valerate provides hormone replacement during and after the climacteric. The addition of levonorgestrel in the second half of each course of tablets helps to provide good cycle control and opposes the development of endometrial hyperplasia.

Most studies show that oral administration of estradiol valerate to post-menopausal women increases serum high density lipoprotein cholesterol (HDL-C) and decreases low density lipoprotein cholesterol (LDL-C). Although epidemiological data are limited such alterations are recognised as potentially protective against the development of arterial disease. A possible attenuation of these effects may occur with the addition of a progestogen. However, at the doses used in FemTab Sequi, the 12 days of combined therapy with estradiol valerate and levonorgestrel have not been observed to be associated with any unwanted lipid effects.

1. Levonorgestrel (LNG)

Orally administered LNG is rapidly and completely absorbed. Following ingestion of one tablet of FemTab Sequi maximum drug serum levels of 1.9ng/ml were found at 1.3 hours. Thereafter, LNG serum levels decrease in two disposition phases. The first phase is described by a half-life of 0.5-1.5 hours and the terminal phase by a half-life of 20-27 hours. For LNG, a metabolic clearance rate from serum of about 1.5 ml/min/kg was determined. LNG is not excreted in unchanged form but as metabolites. LNG metabolites are excreted at about equal proportions with urine and faeces. The biotransformation follows the known pathways of steroid metabolism. No pharmacologically active metabolites are known.

LNG is bound to serum albumin and to SHBG. Only about 1.5% of the total serum drug levels are present as free steroid, but 65% are specifically bound to SHBG. The relative distribution (free, albumin-bound, SHBG-bound) depends on the SHBG concentrations in the serum. Following induction of the binding protein, the SHBG bound fraction increases while the unbound and the albumin-bound fraction decrease.

Following daily repeated administration, LNG concentrations in the serum increase by a factor of about 2. Steady-state conditions are reached within a few days. The pharmacokinetics of LNG is influenced by SHBG serum levels. Under treatment with FemTab Sequi SHBG levels will rise by about 40% during the oestrogen phase and remain constant or slightly decrease thereafter. The absolute bioavailability of LNG was determined to be almost 100% of the dose administered. The relative bioavailability was tested against an aqueous microcrystalline suspension and was found to be complete (108%).

About 0.1% of the maternal dose can be transferred via milk to the nursed infant.

2. Estradiol valerate (E₂ val)

E₂ val is completely absorbed from the FemTab Sequi tablet. During absorption and the first passage through the liver the steroid ester is cleaved into estradiol (E₂) and valeric acid. At the same time E₂ undergoes extensive further metabolism yielding E₂ conjugates, estrone (E₁) and E₁ conjugates. The pharmacologically most active metabolites of E₂ val are E₂ and E₁. Maximum serum levels of 25 pg E₂/ml and 180 pg E₁/ml are reached 5-7 hours after the administration of one FemTab Sequi tablet.

Mean E1 serum levels are 10-12 fold higher than mean E₂ serum concentrations. Serum levels of E₁ conjugates are about 25 fold higher than the E₁ serum levels.

E₂ is rapidly metabolised and the metabolic clearance rate has been determined to 30ml/min/kg. After oral intake of E₂ the half-life of the terminal disposition phase was about 13 hours for E₂. The respective half-life for E₁ serum level decline was about 20 hours. The daily use of FemTab Sequi will lead to an about 50% increase in E₂ serum levels and to twofold E₁ levels at steady state.

Estradiol is bound to about 97% to serum proteins, about 35% are specifically bound to SHBG. E_2- val is not excreted in unchanged form. The metabolites of estradiol are excreted via urine and bile with a half-life of about 1 day at a ratio of 9:1.

The absolute bioavailability of E₂ from E₂ val is about 3% of oral dose and thus in the same range like oral E₂ (5% of dose).

The relative bioavailability of E₂ val (reference: aqueous microcrystalline suspension) from FemTab Sequi tablets was complete (111-112%).

Estradiol and its metabolites are excreted into milk only to a minor extent.

There are no preclinical data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

FemTab Sequi contains the following excipients: lactose, maize starch, povidone 25 000, povidone 700 000, talcum, magnesium stearate (E572), sucrose, macrogol 6000 (polyethylene glycol 6000), calcium carbonate (E170), glycerol (E422), montan glycol wax, yellow and red ferric oxide pigments (E172), titanium dioxide (E171).

Not applicable.

5 years.

None.

Packs containing aluminium foil and PVC blister strips.

Presentation:

Carton containing memo-packs of either 1 x 28 tablets or 3 x 28 tablets.

Not applicable.

Schering Health Care Limited

The Brow

Burgess Hill

West Sussex RH15 9NE

PL 0053/0219

7th October 1991/26^th March 1997

9 December 2003