Orion Pharma (Ireland) Ltd

Indivina 1 mg/2.5 mg tablets

Indivina 1 mg/5 mg tablets

Indivina 2 mg/5 mg tablets

One Indivina 1 mg/2.5 mg tablet contains:

One Indivina 1 mg/5 mg tablet contains:

One Indivina 2 mg/5 mg tablet contains:

For a full list of excipients, see section 6.1.

Tablet.

White, round, bevelled-edge, diameter 7 mm, flat tablets with a code on one side with 1+2.5, 1+ 5, and 2+5, respectively.

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in women with an intact uterus more than three years after menopause.

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.

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

Indivina is a continuous combined HRT regimen in which estrogen and progestagen are given every day without interruption.

Dosage: One tablet each day orally without a tablet-free interval. Tablet should be taken approximately at the same time of the day.

Treatment is recommended to be initiated with Indivina 1 mg/2.5 mg tablet. Depending on the clinical response to treatment, the dosage can then be adjusted to individual needs.

Medroxyprogesterone acetate (MPA) 2.5 mg is usually sufficient to prevent breakthrough bleeding. If breakthrough bleeding occurs and persists, and endometrial abnormality has been ruled out, the dose can be increased to 5 mg (Indivina 1mg/5 mg tablet).

If 1 mg of oestradiol valerate (E₂V) is not sufficient to alleviate estrogen deficiency symptoms, the dose can be increased to 2 mg (Indivina 2 mg/5 mg tablet).

In women with amenorrhea and not taking HRT or women who switch from another continuous combined HRT product, treatment with Indivina may be started on any day. Women who switch from cyclic HRT regimen should start Indivina treatment one week after completion of the cycle.

The effect of estrogen on bone mineral density is dose dependent and therefore the effect of 1 mg E₂V may be less than with 2 mg (see section 5.1).

If the patient has forgotten to take one tablet, the forgotten tablet is to be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

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.

• 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

• Hypersensitivity to the active substances or to any of the excipients

• Porphyria

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 Indivina, 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 (for cyclic or sequential products) or every day (for combination products like Indivina) in non-hysterectomised women greatly reduces this risk.

• Break-through bleeding and spotting may occur during the first months of treatment. If break-through 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-progestogen 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 increases with duration of intake but returns to baseline within a few (at most five) 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- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

• 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 (e.g., 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

• Oestrogens 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 Indivina is increased.

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

• Oestrogens 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.

• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Pregnancy

Indivina is not indicated during pregnancy. If pregnancy occurs during medication with Indivina, treatment should be withdrawn immediately. Data on a limited number of exposed pregnancies indicate adverse effects of medroxyprogesterone acetate on sexual differentiation of the foetus. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

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

Lactation

Indivina is not indicated during lactation.

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

The most frequently reported undesirable effect during Indivina treatment in clinical trials was breast tenderness, which occurred in 10.6% of users.

Undesirable effects according to system organ class associated with Indivina treatment are presented in the table below.

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 epidemilogical 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 trial are presented below:

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

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:

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 and 4.4.

- Myocardial infarction and stroke.

- Gall bladder disease.

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

- Probable dementia (see section 4.4).

Estrogen overdose may cause nausea, headache and uterine bleeding. Numerous reports on high doses of estrogen-containing oral contraceptives ingested by young children indicate that serious harmful effects do not occur. Treatment of estrogen overdose is symptomatic. High doses of medroxyprogesterone acetate (MPA) used for cancer treatment have not resulted in serious undesirable effects.

Pharmacotherapeutic group: Progestagens and estrogens, fixed combinations;

ATC code: G03FA12.

The active form of estradiol valerate, 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.

Medroxyprogesterone acetate is a derivative of the natural progesterone, 17-alpha-hydroxy-6-methylprogesterone. Medroxyprogesterone acetate binds to progestin-specific receptors and acts on the endometrium to convert the status of the endometrium from proliferative to secretory.

As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of medroxyprogesterone acetate greatly reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trial information

Relief of estrogen deficiency symptoms and bleeding patterns

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

Bleeding and/or spotting appeared in 41% of the women receiving 1 mg estradiol valerate and 51% of women receiving 2 mg estradiol valerate during the first three months of treatment and in 9% of the women receiving 1 mg estradiol valerate and in 20% of women receiving 2 mg estradiol valerate during 10-12 months of treatment.

Amenorrhoea was seen in 91% of women receiving 1 mg estradiol valerate and in 80% of women receiving 2 mg estradiol valerate after 10-12 months of treatment.

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 the evidence for that is limited.

After 4 years of treatment with Indivina combinations containing the 1 mg dose, the increase in lumbar spine bone mineral density (BMD) was 6.2 ± 0.5% (mean ± SE). The percentage of women who gained BMD in lumbar zone during treatment was 86.6 %.

Indivina combinations containing the 1 mg dose also had an effect on hip BMD. The increase after 4 years was 2.9 ± 0.4% (mean ± SE) at femoral neck. The percentage of women who gained BMD in hip zone during treatment was 80.4 %.

After 4 years of the treatment with Indivina combinations containing the 2 mg dose, the increase in lumbar spine BMD was 7.4 ± 0.4% (mean ± SE). The percentage of women who gained BMD in lumbar zone during treatment was 95.8 %.

Indivina combinations containing the 2 mg dose also had an effect on hip BMD. The increase after 4 years was 2.9 ± 0.4% (mean ± SE) at femoral neck. The percentage of women who gained BMD in hip zone during treatment was 72.3 %.

Following oral administration estradiol valerate is absorbed from the gastrointestinal tract and rapidly hydrolysed to estradiol by esterases. In postmenopausal women aged 50-65 years the maximum concentration of estradiol in serum (C_max) was reached within 4 to 6 hours after multiple dosing of 1 mg or 2 mg estradiol valerate. After 1 mg dose C_max was about 166 pmol/l, trough concentration (C_min) about 101 pmol/l and average concentration (C_average) about 123 pmol/l. For 2 mg dose C_max was 308 pmol/l, C_min 171 pmol/l and C_average 228 pmol/l. Comparable estradiol concentrations were observed in women over 65 years.

Circulating estradiol is bound to plasma proteins, mainly to sex hormone binding globulin (SHBG) and serum albumin. Estradiol undergoes extensive biotransformation. Its metabolites are excreted in the urine as glucuronide and sulphate conjugates together with a small proportion of unchanged estradiol. Besides urinary excretion, estrogen metabolites undergo an enterohepatic circulation. Only a small amount of a dose is excreted in the faeces.

The absorption of medroxyprogesterone acetate after oral administration is low due to low solubility and there is large individual variation. Medroxyprogesterone acetate undergoes virtually no first-pass metabolism. After multiple dosing of 2.5 mg or 5 mg medroxyprogesterone acetate to women aged 50-65 years, maximum concentration in serum was reached in less than 2 hours. After 2.5 mg dose C_max was about 0.37 ng/ml, C_min about 0.05 ng/ml and C_average about 0.11 ng/ml. After 5 mg dose C_max was about 0.64 ng/ml, C_min about 0.12 ng/ml and C_average about 0.21 ng/ml. Comparable medroxyprogesterone acetate concentrations were observed in women over 65 years.

Medroxyprogesterone acetate is over 90% bound to plasma proteins, mainly to albumin. The elimination half-life of oral medroxyprogesterone acetate is approximately 24 hours. Medroxyprogesterone acetate is extensively metabolised by hepatic hydroxylation and conjugation and excreted in the urine and the bile. Metabolism is poorly documented and the pharmacological activity of the metabolites is not known.

Animal studies with estradiol and medroxyprogesterone acetate have shown expected estrogenic and gestagenic effects. Both compounds induced adverse effects in reproductive toxicity studies. Chiefly, estradiol showed embryotoxic effects and induced feminisation of male foetuses.

Medroxyprogesterone showed embryotoxic effects and induced anti-androgenic effects in male foetuses and masculinization in female foetuses. The relevance of these data for human exposure is unknown (see section 4.6). Concerning other preclinical effects, the toxicity profiles of estradiol valerate and medroxyprogesterone acetate are well known and reveal no particular human health risks beyond those discussed in other sections of the SPC and which generally apply to hormone replacement therapy.

Lactose monohydrate, maize starch, gelatin, magnesium stearate.

Not applicable.

3 years.

Do not store above 30 °C. Store in the original package in order to protect from moisture.

28 tablets in PVC/PVDC/Aluminium blister. Pack of 1x 28 tablets and 3x 28 tablets.

Not all pack sizes may be marketed.

No special requirements.

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

PA1327/005/001

PA1327/005/002

PA1327/005/003

Date of first authorisation: 10 December 1999

Date of last Renewal: 10 December 2009

February 2010