Tridestra

1. Name Of The Medicinal Product

Tridestra

2. Qualitative And Quantitative Composition

Tridestra tablet (white):

Estradiol valerate 2 mg

Tridestra tablet (blue):

Estradiol valerate 2 mg

Medroxyprogesterone acetate 20 mg

Tridestra tablet (yellow):

Placebo

For excipients, see 6.1

3. Pharmaceutical Form

Tablets, oral.

4. Clinical Particulars

4.1 Therapeutic Indications

i) Hormone replacement therapy (HRT) for estrogen deficiency symptoms in peri- and post-menopausal women.

ii) 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.

Please also refer to section 4.4

The experience of treating women older than 65 years is limited.

4.2 Posology And Method Of Administration

Tridestra is a cyclic HRT that produces a vaginal bleed every 3 months. The bleeding occurs during treatment when the yellow (placebo) tablets are taken and is similar to the monthly bleed experienced during the normal menstrual cycle.

Tridestra consists of 91 tablets in a blister pack bearing calendar markings. . Dosage is according to the calendar pack. One tablet should be taken daily without a break between packs.

The dosage during days 1 to 70 (inclusive) of the cycle is 2 mg estradiol valerate (white tablets). From day 71 to day 84 (inclusive) it is 2 mg of estradiol valerate and 20 mg of medroxyprogesterone acetate (blue tablets). From day 85 to day 91 (inclusive) a placebo preparation (yellow tablets) is taken when a menstrual like bleed occurs.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

Women with amenorrhoea who are not taking HRT or who are switching to Tridestra from continuous combined HRT product, may start treatment on any day.

Women who are still having periods may start treatment 5 days after the start of the period.

Women who are switching from a cyclic or sequential HRT product to Tridestra treatment may start one week after completion of the cycle (28 days) ie at the end of a withdrawal bleed.

If the patient has forgotten to take one tablet, it should be taken within 12 hours otherwise the forgotten tablet should be discarded and the usual tablet taken the following day. Missing a dose may increase the likelihood of breakthrough bleeding and spotting.

4.3 Contraindications

• Known, past or suspected breast cancer

• Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)

• Undiagnosed genital bleeding

• Untreated endometrial hyperplasia

• Previous idiopathic or current venous thromboembolism [deep venous thrombosis (DVT), pulmonary embolism]

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

• Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal

• Known hypersensitivity to the active substances or to any of the excipients

• Porphyria

• 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

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast Cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Tridestra, in particular:

• Leiomyoma (uterine fibroids) or endometriosis

• A history of or risk factors for thromboembolic disorders (see below)

• Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

• Hypertension

• Liver disorders (e.g. liver adenoma)

• Diabetes mellitus with or without vascular involvement

• Cholelithiasis

• Migraine or (severe) headache

• Systemic lupus erythematosus

• A history of endometrial hyperplasia (see below)

• Epilepsy

• Asthma

• Otosclerosis

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

• Jaundice or deterioration of liver function

• Significant increase in blood pressure

• New onset of migraine-type headache

• Pregnancy

Endometrial hyperplasia

• The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see Section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

• Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time of therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to excluded endometrial malignancy.

Breast cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI) and epidemiological studies including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increase with duration of intake but returns to baseline within a few (at most 5 years) after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

• HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two

• 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.

• Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, 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 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

• If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD)

• There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity and mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

• One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

• Long-term (at least 5-10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.

Other conditions

• Estrogens may cause fluid retention and, therefore, patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients of Tridestra is increased.

• Women with pre-existing hypertriglyceridaemia should be followed closely during estrogen replacement or HRT, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

• Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

• There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of estrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

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 estrogens and progestogens.

Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

4.6 Pregnancy And Lactation

Tridestra is not indicated during pregnancy. If pregnancy occurs during medication with Tridestra treatment should be withdrawn immediately.

Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of medroxyprogesterone acetate on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestogen indicate no teratogenic or foetotoxic effect.

Lactation

Tridestra is not indicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

No effects on ability to drive and use machines have been observed

4.8 Undesirable Effects

Adverse drug reactions occur most commonly in the first months of the treatment. The most common adverse effect is breakthrough bleeding and spotting appearing in 22% of patients. The overall percentage of treated patients experiencing at least 1 adverse reaction is 47%.

Organ group	Common (>1/100)	Uncommon >1/1,000, <1/100	Rare >1/10,000; <1/1,000
Gastrointestinal disorders	Nausea, abdominal pain	vomiting
Skin and subcutaneous tissue disorders
Nervous System disorders	Headache, migraine
Vision disorders	Visual disturbances
Cardiac and vascular disorders
Reproductive disorders and breast disorders	Dysmenorrhoea, breast tenderness, breast enlargement, breakthrough bleeding.	Uterine fibroids	Endometrial hyperplasia, menorrhagia
Miscellaneous	Oedema, tiredness, weight increase, changes in mood, changes in libido

Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was estrogen only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95% CI 1.21-1.49) and 1.30 (95% CI 1.21-1.40), respectively.

For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88-2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95% CI: 1.01-1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trials are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

• For users of estrogen only replacement therapy,

• between 0 and 3 (best estimate = 1.5) for 5 years' use • between 3 and 7 (best estimate = 5) for 10 years' use.

• For users of estrogen plus progestagen combined HRT,

• between 5 and 7 (best estimate = 6) for 5 years' use • between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group,

• about 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be

• between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).'

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with estrogen/progestagen treatment:

• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer.

• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information see sections 4.3. Contraindications and 4.4. Special warnings and precautions for use.

• Myocardial infarction and stroke.

• Gall bladder disease.

• Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

• Probable dementia (see section 4.4)

4.9 Overdose

Overdosage of estrogen may cause nausea, headache and withdrawal bleeding. Serious ill effects have not been reported following acute ingestion of large doses of estrogens and progestogens in contraceptive formulations by young children. When needed, therapy is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Progestogens and Estrogens in Combination

ATC code: G03FB 06

•Estradiol / Estradiol valerate: the active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

Progestagen: Medroxyprogesterone acetate (MPA) is a synthetic derivative of natural progesterone, a 17-α-hydroxy-6-methylprogesterone acetate. It has a similar effect to progesterone with slight androgenic activity. As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

•Relief of estrogen-deficiency symptoms and bleeding patterns

- Relief of menopausal symptoms was achieved during the first few weeks of treatment.

- Tridestra causes a withdrawal bleed at the end of a 3 monthly cycle

- Regular withdrawal bleeding occurred in 77% of women with a mean duration of 5 days. Withdrawal bleeding usually started 2-3 days after the last tablet is taken of the 14 days of the estrogen/progestagen phase (2 mg E₂V + 20 mg MPA). Break through bleeding and/or spotting appeared in 15% of the women during the first three months of therapy and in 27% during months 10-12 of treatment. Amenorrhoea (no bleeding or spotting) occurred in 0% of the cycles during the first year of treatment (for cyclic or sequential products).

•Prevention of osteoporosis

- Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on bone mineral density (BMD) is dose dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

- Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but evidence for that is limited.

- After 1 year of treatment with Tridestra, the increase in lumbar spine bone mineral density (BMD) was 3.3 ± 3.6 % (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 72.7%. After 2 years of treatment with Tridestra, the increase in BMD was 5.9 ± 3.0 % (mean ± SD). The percentage of women who maintained or gained BMD in lumber zone during treatment was 95.2%.

- Tridestra also had an effect on hip BMD. The increase after 1 year was 2.3% ± 3.4% (mean ± SD) at the femoral neck. The percentage of women who maintained or gained BMD in the hip zone during treatment was 72.7%. The increase after 2 years was 0.6% ± 3.6% (mean ± SD) at femoral neck. The percentage of women who maintained or gained BMD in the hip zone during treatment was 52.4%.

5.2 Pharmacokinetic Properties

Maximum plasma levels (C_max) of estradiol (about 250 pmol/l) are reached in about 5-7 hours. The trough concentration (C_min) of estradiol was about 142 pmol/l and the average concentration (C_average) about 185 pmol/l. In circulation, natural estrogens are bound to sex hormone binding globulin and albumin. Free estradiol is metabolised in the liver and partly converted to less active estrogens like estrone.

Maximum plasma levels (C_max) of estrone (about 1790 pmol/l) are reached in 5–7 hours after intake of the tablet. C_min of estrone was about 864 pmol/l, C_average about 1160 pmol/l. Estrone is subjected to an enterohepatic cycle and its half-life is 15–20 hours. The majority of estrogens are excreted via kidneys as conjugates (sulphates or glucuronides).

MPA is well absorbed from the gastrointestinal tract and rapidly distributed from circulation to extravascular tissues. After the intake of the Tridestra combination tablet, the maximum plasma level (C_max) of MPA (about 5 μg/L) is reached in about 2 hours. C_average (after a single dose) was about 1.3 μg/L. The elimination half-life is 40-50 hours. MPA is metabolised in the liver and excreted as glucuronides both in urine and bile. The extent of absorption from the combination tablet is comparable to MPA given alone.

5.3 Preclinical Safety Data

Data from animal toxicity studies with estradiol and medroxyprogesterone acetate have shown expected estrogenic and gestagenic effects, and do not reveal any particular risk for humans in the therapeutic dose-range..

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tridestra tablet (white):

Lactose

Maize starch

Gelatine

Purified water

Magnesium stearate

Talc

Tridestra tablet (blue):

Lactose

Maize starch

Gelatine

Purified water

Magnesium stearate

Indigo carmine (E132)

Tridestra tablet (yellow):

Lactose

Maize starch

Gelatine

Purified water

Magnesium stearate

Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25 ^oC

Store in a dry place

6.5 Nature And Contents Of Container

A PVC/PVDC/AL thermofoiled blister pack.

Quantity: 91

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Orion Corporation

P.O.Box 65,

FIN-02101 Espoo

Finland

8. Marketing Authorisation Number(S)

PL 27925/0014

9. Date Of First Authorisation/Renewal Of The Authorisation

11/01/2006

10. Date Of Revision Of The Text

11/01/2006