Trisequens

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 07/06/17

files-icon(Click to Download)
Summary of Product Characteristics last updated on medicines.ie: 20/4/2016
print

Print ViewKeyword Search SmPC

Novo Nordisk Limited

Novo Nordisk Limited

Company Products

Medicine NameActive Ingredients
Medicine Name Activelle Active Ingredients Estradiol Hemihydrate, Norethisterone acetate
Medicine Name Actrapid 100 international units/ml, Solution for injection in a vial Active Ingredients Human Insulin
Medicine Name Estrofem 2mg Active Ingredients Estradiol Hemihydrate
Medicine Name Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen Active Ingredients Insulin aspart
Medicine Name Fiasp 100 units/mL Penfill solution for injection in cartridge Active Ingredients Insulin aspart
Medicine Name Fiasp 100 units/mL solution for injection in vial Active Ingredients Insulin aspart
Medicine Name GlucaGen HypoKit 1 mg powder and solvent for solution for injection Active Ingredients Glucagon hydrochloride
Medicine Name Insulatard 10 ml Vial Active Ingredients Human Insulin
Medicine Name Insulatard InnoLet Active Ingredients Human Insulin
Medicine Name Insulatard Penfill Active Ingredients Human Insulin
Medicine Name Insulatard, Insulatard Penfill, Insulatard InnoLet Active Ingredients Human Insulin
Medicine Name Kliogest 2 mg/1 mg film-coated tablets Active Ingredients Estradiol Hemihydrate, Norethisterone acetate
Medicine Name Levemir FlexPen (Insulin detemir) 100 units/ml solution for injection in pre-filled pen Active Ingredients insulin detemir
Medicine Name Levemir InnoLet (Insulin detemir) 100 units/ml solution for injection in pre-filled pen Active Ingredients insulin detemir
Medicine Name Levemir Penfill (Insulin detemir) 100 units/ml solution for injection in cartridge Active Ingredients insulin detemir
Medicine Name Norditropin FlexPro 10 mg/1.5 ml solution for injection in pre-filled pen Active Ingredients Somatropin
Medicine Name Norditropin FlexPro 15 mg/1.5 ml solution for injection in pre-filled pen Active Ingredients Somatropin
Medicine Name Norditropin FlexPro 5 mg/1.5 ml solution for injection in pre-filled pen Active Ingredients Somatropin
Medicine Name Norditropin SimpleXx 10 mg/1.5 ml, solution for injection Active Ingredients Somatropin
Medicine Name Norditropin SimpleXx 15 mg/1.5 ml, solution for injection Active Ingredients Somatropin
Medicine Name Norditropin SimpleXx 5 mg/1.5 ml, solution for injection in cartridge Active Ingredients Somatropin
Medicine Name Novofem film-coated tablets Active Ingredients Estradiol Hemihydrate, Norethisterone acetate
Medicine Name NovoMix 30 FlexPen Active Ingredients Insulin aspart
Medicine Name NovoMix 30 Penfill Active Ingredients Insulin aspart
Medicine Name NovoNorm 0.5 mg, 1 mg and 2 mg tablets Active Ingredients Repaglinide
1 - 0 of 40 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 7 June 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 7 June 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 20 April 2016 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 20 April 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 20 April 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.4  

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

 

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI trial, suggest that the long-term use of combined HRT may confer a similar or slightly smaller risk (see section 4.8).

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).


Section 4.8

Ovarian cancer risk

Long-term useUse of oestrogen-only andor combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer. In the Million Women Study, diagnosed (see section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRTresultedthis results in about 1 extra case per 2,500 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period.


Section 10

October 2015April 2016

Updated on 28 October 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.1       Therapeutic indications
"also" was deleted from: (see also section 4.4).
4.2 Posology and method of administration
"also" was deleted from: (see also section 4.4).
4.4       Special warnings and precautions for use
text inserted:
"Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women."
wording changed from: "venous thromboembolism" to "VTE"
4.5       Interaction with other medicinal products and other forms of interaction
word "telaprevir" deleted  after "efavirenz"
4.6       Fertility, pregnancy and lactation
Word "those" deleted. THe sentence now reads: "At doses higher than normally used in OC and HRT formulations, masculinisation of female foetuses was observed."
4.8 Undesirable effects
Wording "Breast pain disappears ..." - word "disappears" deleted, "disappeared" included instead.
10.       DATE OF REVISION OF THE TEXT
date inserted: October 2015

Updated on 27 October 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 21 August 2014 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

2.                     QUALITATIVE AND QUANTITATIVE COMPOSITION

 

                        Each film-coated tablet contains:

Trisequens

 

Blue tablet: Estradiol 2 mg (as estradiol hemihydrate).

 

White tablet: Estradiol 2 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg.

 

Red tablet: Estradiol 1 mg (as estradiol hemihydrate).

 

Excipient: Each Blue tablet contains 36.8mg lactose monohydrate. Each White tablet contains 36.3mg lactose monohydrate. Each Red tablet contains 37.3mg lactose monohydrate.

For a the full list of excipients, see section 6.1.

3.                     PHARMACEUTICAL FORM

 

Film-coated tablets.

 

                        Blue film-coated, biconvex tablets engraved with NOVO 280.  Diameter: 6 mm.

 

                        White film-coated, biconvex tablets engraved with NOVO 281.  Diameter: 6 mm.

 

                        Red film-coated, biconvex tablets engraved with NOVO 282.  Diameter: 6 mm.

4.1       Therapeutic indications

 

Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women with at least 6 months since last menses.

4.2    Posology and method of administration

 

Trisequens is a continuous sequential preparation for HRT product. The oestrogen is dosed continuously. The progestagen is added for 10 days of every 28 day cycle, in a sequential manner.

One tablet should be taken orally once a day without interruption, preferably at the same time of the day starting with oestrogen therapy (blue film-coated tablet) over 12 days, followed by 10 days of oestrogen/progestagen therapy (white film-coated tablet) and 6 days of oestrogen therapy (red film-coated tablet). A regular shedding of the endometrium is usually induced during the red tablet phase.

After intake of the last red tablet, treatment is continued with the first blue tablet of a new pack on the next day.

In women who are not taking HRT or women in transition transferring from a continuous combined HRT product, treatment with Trisequens may be started on any convenient day. In women in transition transferring in transition from another sequential HRT regimen, treatment should begin the day following completion of the priorpreceding regimen.
...................

How to use the calendar pack  

 

1. Set the day reminder

Turn the inner disc to set the wanted day of the week opposite the little plastic tab.

 

2. Take the first day’s tablet

Break the plastic tab and tip out the first tablet (blue)

 

3. Move the dial every day

On the next day simply move the transparent dial clockwise one space as indicated by the arrow. Tip out the next tablet. Remember to take only one tablet once a day.

4.3       Contraindications

 

            -           Known, past or suspected breast cancer
            -           Known, past or suspected oestrogen-dependent malignant tumours (e.g.  endometrial cancer)

 

            -           Undiagnosed genital bleeding

 

            -           Untreated endometrial hyperplasia

 

            -           Previous idiopathic or current venous thromboembolism (deep venous                                                                          thrombosis, pulmonary embolism)

 

            -           Active or previous arterial thromboembolic disease (e.g. angina, myocardial infarction)

 

            -           Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency (see section 4.4))

 

            -           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.

4.4       Special warnings and precautions for use

 

Endometrial hyperplasia and carcinoma

 

In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment, the risk may remain elevated for a number of years. In some studies the risk remained elevated more than 10 years off oestrogen.
....
Breast Ccancer
..........

The randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen HRT that becomes apparent after about 3 years (see section 4.8).

 

The excess risk becomes apparent within a few after abou 3 years of use, but returns to baseline within a few years (at most 5) years after stopping treatment.
..........

In women with no personal history of VTE but with a first degree relative with a history of venous thromboembolismsis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).

 

If a thrombophilic defect is identified which segregates with venous thromboembolismthrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

.........

Coronary artery disease (CAD)

 

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined conjugated oestrogen-progestagen
.........

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

 

Patients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on HRT to ensure that thyroid hormone levels remain in an acceptable range.

Oestrogens increase thyroid binding globulin (TGBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radioimmunoassay).  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 biologically active hormone concentrations are unchanged.  Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin and, ceruloplasmin).

..........
Trisequens has no contraceptive effect. Hormonal contraception should be stopped when the use of Trisequens is started and the patient should be advised to take non-hormonal contraceptive precautions if required.
.............

4.5       Interaction with other medicinal products and other forms of interaction

 

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

Ritonavir, telaprevir 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 oestrogens and progestagens.
...........

Reduced estradiol levels have been observed under the simultaneous use of antibiotics e.g. penicillins and tetracycline.
..........

Oral contraceptives (OC) containing ethinylestradiol have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered. Similar interaction may exist between HRT containing estradiol and lamotrigine. Therefore, dosage adjustment of lamotrigine may be necessary for seizure control.
..........

Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or thyroid function
...........

4.6       Fertility, pregnancy and lactation

 

                        Pregnancy
..............

 

....placebo, and which on an overall judgement are possibly related to treatment are presented below in the table below:
.............

 

Endometrial

hyperplasia

Dysmenorrhoea, see also back pain under

Musculoskeletal,

connective tissue

and bone

disorders and abdominal pain under

Gastrointestinal

 

disorders
...................

 

Hepatobiliary disorders: Gall bladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis reoccurrence

 

•        Skin and subcutaneous tissue disorders: Seborrhoea, rash, angioneurotic oedema

 

•        Reproductive system and breast disorders: Endometrial hyperplasia endometiral, vulvovaginal pruritus

 

•        Investigations: Weight decreased, blood pressure increased.

 

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:The following adverse reactions have been reported in association with other oestrogen-progestagen treatment:

...................
Additional CasesIncidence per 1,000 never-users of HRT over a 5 years* period
Risk ratio  and 95% CI**

CEE+MPA oestrogen-progestagen**

50-79

174

1.2 (1.0-1.5)

4 (0-9)

...................

 

WHI Studies – Additional risk of VTE over 5 years’ use

 

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users over 5 years’ use (95% CI)

...............

WHI Studies Combined – Additional risk of ischaemic stroke* over 5 years’ use

 

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users over 5 years’ use (95% CI)

...........

* No differentiation was made between ischaemic and haemorrhagic stroke.

 

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

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie.

 

..............

5.                     PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

   Pharmacotherapeutic group: Progestagens and oestrogens, sequential preparations, ATC code G03FB05.
...............

addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
...............

Regular withdrawal bleeding occurred in 93% of the women with a mean duration of 3-4 days.

 

Oestrogen deficiency at menopause is associated with an increased increasing bone turnover and decline in bone mass.
............

Evidence from the WHI trial and meta-analysis of analysed trials show that current use of HRT, oestrogen 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.

 

Studies based on  the measurement of bone mineral content have shown that Trisequens is effective in the prevention of osteoporosis in postmenopausal women. After 2 years of treatment, bone mineral density in the spine had increased by 5.14% and in the hip by 3.21%.
...............

5.2       Pharmacokinetic properties
...... including oestrone, catecholoestrogens and several oestrogen sulfphates and glucuronides. Oestrogens are excreted with the bile, where they are hydrolysed and reabsorbed (enterohepatic circulation), and mainly eliminated in urine in biologically inactive form.
........
........which are excreted mainly in the urine as sulphfate or glucuronide conjugates.

 

The pharmacokinetics of estradiol is not influenced by norethisterone acetate.

 

The pharmacokinetic properties in the elderly hasve not been studied.

 

5.3       Preclinical safety data

 

The toxicity profiles of estradiol and norethisterone acetate are well known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC Summary of Product Characteristics.
..............

6.4       Special precautions for storage

 

Store below 25°C. Do not refrigerate. Keep the container in the outer carton in order to protect it from light.

6.5       Nature and contents of container

 

1 x 28 tablets in calendar dial packs.

 

The calendar dial pack with 28 tablets consists of the following 3 parts:

 

-             The base made of coloured non-transparent polypropylene.

 

-             The ring-shaped lid made of transparent polystyrene.

 

-             The centreal-dial made of coloured non-transparent polystyrene.

 

 

 

6.6     Special precautions for disposal and other handling

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. No special requirements.
...........

 

10.       DATE OF REVISION OF THE TEXT

August 201412/2011

 

Updated on 18 August 2014 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to instructions about missed dose
  • Change to side-effects
  • Change to drug interactions
  • Change to further information section
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 25 September 2012 PIL

Reasons for updating

  • Change to MA holder contact details

Updated on 20 December 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4 - Clinical particulars
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

                        Each film-coated tablet contains:

 

                        Trisequens

Blue tablet: Estradiol hemihydrate corresponding to estradiol 2 mg (as estradiol hemihydrate)..

White tablet: Estradiol hemihydrate corresponding to estradiol 2 mg (as estradiol hemihydrate) and

Nnorethisterone acetate 1 mg.

Red tablet: Estradiol hemihydrate corresponding to estradiol 1 mg (as estradiol hemihydrate).

Excipients: Each tablet contains approximately 38mg lactose monohydrate.

Each Blue tablet contains 36.8mg lactose monohydrate. Each White tablet contains 36.3mg lactose monohydrate. Each Red tablet contains 37.3mg lactose monohydrate.

 

4.1       Therapeutic indications

Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women at least 6 months since last menses.

 

4.2    Posology and method of administration

 

Trisequens is a continuous sequential preparation for HRT. The oestrogen is dosed continuously. The progestagen is added for 10 days of every 28 day cycle, in a sequential manner.

One tablet should be taken orally once a day without interruption, preferably at the same time of the day starting with oestrogen therapy (blue film-coated tablet) over 12 days, followed by 10 days of oestrogen/progestagen therapy (white film-coated tablet) and 6 days of oestrogen therapy (red film-coated tablet). A regular shedding of the endometrium is usually induced during the red tablet phase.

After intake of the last red tablet, treatment is continued with the first blue tablet of a new pack on the next day.

In women who are not taking HRT or women transferring from a continuous combined HRT product, treatment with Trisequens may be started on any convenient day. In women transferring from another sequential HRT regimen, treatment should begin the day following completion of the prior regimen.

Trisequens® is administered orally, one tablet daily without interruption. If the women are still having regular periods or transferring from another sequential HRT, treatment is started on day 5 of bleeding. In women with amenorrhoea and not taking HRT or women with irregular periods or women transferring from a continuous combined HRT product treatment with Trisequens® may be started on any convenient day.

 

Trisequens® is a triphasic oestrogen/progestogen with 10 days of progestogen in each 28 day cycle. Trisequens® contains the oestrogen 17b-oestradiol and the progestogen norethisterone acetate. The addition of a progestogen for 10 days during each cycle in the majority of women induces a regular shedding of the endometrium. Regular withdrawal bleeding will be established, usually during the administration of the ‘low dose oestrogen tablets’, i.e. the 6 red tablets or possibly even during the last few of the white tablets.

 

The low oestrogen content in the last series of tablets may prevent the reappearance of climacteric symptoms without affecting the withdrawal bleeding.

 

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.

 

A switch to a higher dose combination product could be indicated if the response after three months is insufficient for satisfactory symptom relief.

 

If athe patient has forgetsforgotten to take a tablet, the tablet should be taken as soon as possible within the next 12 hours. If more than 12 hours have passed, the the forgotten tablet should be discarded. Forgetting a tablet dose may increase the likelihood of breakthrough bleeding and spotting.

 

How to use the calendar pack    

 

1. Set the day reminder

Turn the inner disc to set the wanted day of the week opposite the little plastic tab.

 

2. Take the first day’s tablet

Break the plastic tab and tip out the first tablet (blue)

 

3. Move the dial every day

On the next day simply move the transparent dial clockwise one space as indicated by the arrow. Tip out the next tablet. Remember to take only one tablet once a day.

 

4.3       Contraindications

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

            -           Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency (see section 4.4)).

 

4.4       Special warnings and precautions for use

 

Endometrial hyperplasia and carcinoma

 

In women with an intact uterus, Tthe risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment, the risk may remain elevated for a number of years. In some studies the risk remained elevated more than 10 years off oestrogen. in non-hysterectomised women (see section 4.8).

 

The addition of a progestogenprogestagen cyclically for at least 10 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excessgreatly reduces this risk associated with oestrogen-only HRT.

 

Break-through bleeding and spotting may occur during the first months of treatment in women with intact uterus.  If break-through bleeding or spotting continues after the first months of treatment, appears after some time on during therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast Cancer

 

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT that is dependent on the duration of taking HRT.

 

TheA randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), are consistent in finding have reported an increased risk of breast cancer in women taking combined oestrogens, oestrogen-progestogenprogestagen combinations or tibolone for HRT for several years (see Ssection 4.8).

 

 For all HRT, anThe excess risk becomes apparent within a fewafter about 3 years of use,  and increases with duration of intake but returns to baseline within a few (at most five) years (at most 5) after stopping treatment.

 

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

 

In the WHI study, the continuous combined conjugated equine oestrogen 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 oestrogen-progestoagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

 

Ovarian cancer

 

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI trial, suggest that the long-term use of combined HRT may confer a similar, or slightly smaller risk (see section 4.8).

 

                        Venous thromboembolism

 

HRT is associated with a 1.3- to 3-fold 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 (see section 4.8).

 

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).

 

                       

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, a personal history or family history, severe obesity (BMI > 30 kg/m2), pregnancy/postpartum period, and  systemic lupus erythematosus (SLE) and cancer.  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 need to be considered to prevent VTE following surgery.  IfWhere 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 possibles recommended.  Treatment should not be restarted until the woman is completely mobilised.

 

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).

 

If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

 

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

 

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, dyspnoea).

 

          Coronary artery disease (CAD)

 

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received cardiovascular benefit with continuous combined conjugated oestrogen-progestagen or oestrogen-only HRT. The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age. s 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 or mortality. Therefore it is uncertain whether these findings also extend to other HRT products.

 

 

Ischaemic Sstroke

 

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

 

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 oestrogens 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 oestrogens 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 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 or 10 years) use of estrogen-only HRTs and estrogen plus progestogen HRTs has been associated with an increased risk of ovarian cancer in some epidemiological studies.

 

   Other conditions

 

- Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. 

Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

Patients with terminal renal insufficiency should be closely observed since it is expected that the level of circulating active ingredients in Trisequens® will be increased.

 

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

 

Patients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on HRT to ensure that thyroid hormone levels remain in an acceptable range.

 

- Oestrogens increase thyroid binding globulin (TGB), 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 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 biologically active hormone concentrations are unchanged.  Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

 

HRT use does not- 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 or oestrogen-only HRT after the age of 65.

 

Trisequens has no contraceptive effect. Hormonal contraception should be stopped when the use of Trisequens is started and the patient should be advised to take non-hormonal contraceptive precautions if required.

CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

 

- Trisequens® tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 

 

4.5       Interaction with other medicinal products and other forms of interactions

 

 The metabolism of oestrogens and progestogenprogestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes such as meprobamate, phenylbutazone, anticonvulsants (e.g. Pphenobarbital, 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 oestrogens and progestogenprogestagens.

 

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

 

Reduced estradiol levels have been observed under the simultaneous use of antibiotics e.g. penicillins and tetracycline.

 

Drugs that inhibit the activity of hepatic microsomal drug metabolising enzymes, e.g. ketoconazole, may increase circulating levels of the active substances in Trisequens®.

 

Oral contraceptives (OC) containing ethinylestradiol have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered. Similar interaction may exist between HRT containing estradiol and lamotrigine. Therefore, dosage adjustment of lamotrigine may be necessary for seizure control.

 

Concomitant administration of cyclosporine may cause increased blood levels of cyclosporine, creatinine and transaminases due to decreased metabolism of cyclosporine in the liver.

 

Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or thyroid function.

 

 

4.8         Undesirable effects

 

Post-marketing experience

 

In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported, and are by an overall judgment considered possibly related to Trisequens treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (< 1/10,000, not known (cannot be estimated from the available data)). Post-marketing experience is subject to underreporting especially with regard to trivial and well known adverse drug reactions. The presented frequencies should be interpreted in that light:

 

        Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer

        Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock)

 

        Psychiatric disorders: Insomnia, anxiety, libido decreased, libido increased

        Nervous system disorders: Dizziness, stroke

        Eye disorders: Visual disturbances

        Cardiac disorders: Myocardial infarction

        Vascular disorders: Hypertension aggravated

        Gastrointestinal disorders: Dyspepsia, vomiting

        Hepatobiliary disorders: Gallbladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis reoccurrence

        Skin and subcutaneous tissue disorders: Seborrhoea, rash, angioneurotic oedema

        Reproductive system and breast disorders: Hyperplasia endometrial, vulvovaginal pruritus

        Investigations: Weight decreased, blood pressure increased

 

The following adverse reactions have been reported in association with other oestrogen-progestagen treatment:

·        Skin and subcutaneous disorders: Alopecia, chloasma, erythema multiforme, erythema nodosum, vascular purpura

·        Probable dementia over the age of 65 (see section 4.4)

 

Breast cancer risk

 

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 oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was oestrogen-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 oestrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

 

The MWS reported that, compared to never users, the use of various types of oestrogen-progestogen combined HRT was associated with a higher risk of breast  cancer (RR = 2.00, 95% CI: 1.88-2.12) than use of oestrogens 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 oestrogen-progestogen 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:

• 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 oestrogen-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 oestrogen plus progestogen 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 oestrogen-progestogen 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 oestrogen + progestogen 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). An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.

 

Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations.

 

The level of risk is dependent on the duration of use (see section 4.4).

 

Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented below.

 

Million Women Study – Estimated additional risk of breast cancer after 5 years’ use

 

Age range (years)

Additional cases per 1,000 never-users of HRT over a 5 year period*

Risk ratio and 95% CI**

Additional cases per 1,000 HRT users over 5 years’ use (95% CI)

Oestrogen-only HRT

50-65

9-12

1.2

1-2 (0-3)

Combined oestrogen-progestagen

50-65

9-12

1.7

6 (5-7)

* Taken from baseline incidence rates in developed countries

** Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionally.

 

US WHI Studies – Additional risk of breast cancer after 5 years’ use

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users over 5 years (95% CI)

CEE oestrogen-only

50-79

21

0.8 (0.7-1.0)

-4 (-6-0)*

CEE+MPA oestrogen-progestagen**

50-79

14

1.2 (1.0-1.5)

4 (0-9)

* WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

** When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment. After 5 years the risk was higher than in non-users.

 

 

 

Endometrial cancer risk

 

The endometrial cancer risk is about 5 in every 1,000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiological studies varied from between 5 and 55 extra cases diagnosed in every 1,000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study, the use of 5 years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer risk

 

Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study, 5 years of HRT resulted in 1 extra case per 2,500 users.

 

Risk of venous thromboembolism

 

HRT is associated with a 1.3- to 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT (see section 4.4). Results of the WHI studies are presented below.

 

WHI Studies – Additional risk of VTE over 5 years’ use

 

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users

Oral oestrogen-only*

50-59

7

1.2 (0.6-2.4)

1 (-3-10)

Oral combined oestrogen-progestagen

50-59

4

2.3 (1.2-4.3)

5 (1-13)

* Study in women with no uterus

 

Risk of coronary artery disease

 

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).

 

Risk of ischaemic stroke

 

The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

 

This relative risk is not dependent on age or on duration of use, but the baseline risk is strongly age-dependent. The overall risk of stroke in women who use HRT will increase with age (see section 4.4).

 

WHI Studies Combined – Additional risk of ischaemic stroke* over 5 years’ use

 

Age range (years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio and 95% CI

Additional cases per 1,000 HRT users over 5 years

50-59

8

1.3 (1.1-1.6)

3 (1-5)

·        No differentiation was made between ischaemic and haemorrhagic stroke

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. 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 oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestogen to oestrogen-only therapy greatly reduces this increased risk.

 

Post marketing experience:

 

In addition to the above-mentioned adverse drug reactions, those presented below have been spontaneously reported, and are by an overall judgement considered possibly related to Trisequens® treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (<1/10,000 patient years):

 

- Neoplasms benign and malignant (incl. cysts and polyps): Endometrial cancer

- Psychiatric disorders: Insomnia, anxiety, libido decreased, libido increased

- Nervous system disorders: Dizziness, stroke

- Eye disorders: Visual disturbances

- Vascular disorders: Hypertension aggravated

- Cardiac disorders: Myocardial infarction

- Gastrointestinal disorders: Dyspepsia, vomiting

- Hepatobiliary disorders: Gallbladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis re-occurrence

- Skin and subcutaneous tissue disorders: Seborrhoea, rash, angioneurotic oedema

- Reproductive system and breast disorders: Vulvovaginal pruritus

- Investigations: Weight decreased, blood pressure increased.

 

The following adverse reactions have been reported in association with oestrogen/progestogen treatment:

 

- Skin and subcutaneous tissue disorders: Chloasma, erythema multiforme, erythema nodosum, vascular purpura

- Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock)

- Probable dementia (see section 4.4).

 

 

5.                     PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

   Pharmacotherapeutic group: progestagens and oestrogens, sequential preparations, ATC code G03F B05

 

Oestrogen and progestogen for continuous sequential hormone replacement therapy (HRT).

 

Estradiol: The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.

 

Oestrogens prevent bone loss following menopause or ovariectomy.

 

Norethisterone acetate: Synthetic progestagen with actions similar to those of progesterone, a natural female sex hormone. As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer.

 The addition of a progestogenprogestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

 

 

6.4       Special precautions for storage

 

Store below 25°C.Do not store above 25ºC Do not refrigerate. Keep the container in the outer carton in order to protect from light.

 

6.5       Nature and contents of container

 

1 x 28 tablets in calendar dial packs.

 

The calendar dial pack with 28 tablets consists of the following three  3 parts:

 

- The base made of coloured non-transparent polypropylene

 

- The ring-shaped lid made of transparent polystyrene

 

- The central-dial made of coloured non-transparent polystyrene

 

 

 

6.6     Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

 

No special requirements.                       How to use the calendar pack  

 

1. Set the day reminder

Turn the inner disc to set the wanted day of the week opposite the little plastic tab.

 

2. Take the first day’s tablet

Break the plastic tab and tip out the first tablet (blue)

 

3. Move the dial every day

On the next day simply move the transparent dial clockwise one space as indicated by the arrow. Tip out the next tablet. Remember to take only one tablet once a day.

 

 

10.       DATE OF REVISION OF THE TEXT

 

MM/YYYY12/2011

Updated on 16 December 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to storage instructions
  • Change to side-effects
  • Change to drug interactions
  • Change to date of revision
  • Change due to user-testing of patient information

Updated on 30 March 2011 PIL

Reasons for updating

  • Change to improve clarity and readability

Updated on 5 August 2010 SmPC

Reasons for updating

  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

SmPC changes for Trisequens

 

Gelatine Substitution

 

 

PREVIOUS WORDING

NEW WORDING

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipients: Each tablet contains approximately 38mg lactose monohydrate.

2.      QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Excipients: Each tablet contains approximately 37mg lactose monohydrate.

 

 

4.4  Special warnings and precautions for use

 

4.4  Special warnings and precautions for use

 

Ovarian cancer

Use of estrogen alone and estrogen plus progestogen therapies for at least 5 or 10 years has been associated with an increased risk of ovarian cancer in some epidemiological studies.

 

Ovarian cancer

Use of oestrogen alone and oestrogen plus progestogen therapies for at least 5 or 10 years has been associated with an increased risk of ovarian cancer in some epidemiological studies.

 

4.5    Interaction with other medicinal products and other forms of interaction

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 oestrogens and progestogens.

 

 

4.5    Interaction with other medicinal products and other forms of interaction

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 oestrogens and progestogens.

 

 

4.8    Undesirable effects

Breast cancer

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 oestrogen-progestogen 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 oestrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

- between 0 and 9 (best estimate = 4) for 5 years’ use.

 

4.8    Undesirable effects

Breast cancer

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 oestrogen-progestogen 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 oestrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be between 0 and 9 (best estimate = 4) for 5 years’ use.

 

 

 

6.1  List of Excipients

 

Gelatin

 

Blue tablets:          Indigotin E132

 

6.1  List of Excipients

 

Hydroxypropylcellulose

 

Blue tablets:          Indigo carmine E132       

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation: 21st May 1977

Date of last renewal: 21st May 2007

 

 

9.      DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 May 1977

        Date of last renewal: 21 May 2007

10.  DATE OF REVISION OF THE TEXT

October 2009

 

10.    DATE OF REVISION OF THE TEXT

July 2010

 

 

 

 

 

Updated on 19 March 2010 SmPC

Reasons for updating

  • Correction of spelling/typing errors
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Minor spelling and grammar corrections in secitons 3,4.2,4.8,5.1,6.1 and 8.
Change of date for Revision of text from Aug 2008 to Oct 2009.

Updated on 10 February 2010 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 19 January 2010 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 5 June 2009 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Under Excipients: added sentence "Each tablet contains approximately 38mg" lactose monohydrate.

Updated on 30 October 2008 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.4 - Special precautions for storage

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

2.      Qualitative and Quantitative Composition

Excipients: Each tablet contains approximately 38mg lactose monohydrate.

Has been changed to the following: Excipients: lactose monohydrate

 4.4    Special warnings and precautions for use

Ovarian cancer

 The following text has been deleted: Long term (at least 5-10 years) use of oestrogen-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 oestrogen-only products.

 The following text has been added: Use of estrogen alone and estrogen plus progestogen therapies for at least 5 or 10 years has been associated with an increased risk of ovarian cancer in some epidemiological studies.

 6.4    Special precautions for storage

 Store in the original package.  Do not store above 25C.  Do not refrigerate or freeze.

 The text above has been replaced with the following text: Do not store above 25C.  Do not refrigerate. Keep the container in the outer carton in order to protect from light.

Updated on 27 August 2008 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.1 - List of excipients
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 7 - Marketing authorisation holder
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 1: Heading changed to  "NAME OF THE MEDICINAL PRODUCT"
 
Section 2: Text added: “Excipients: Each tablet contains approximately 38mg lactose monohydrate.”
 
Section 2:  “For excipients, see section 6.1.” amended to “For a full list of excipients, see section 6.1.”
 
Section 3: “(tablet).” has been added to read  “Film-coated tablet (tablet).”
 
Section 4: Under "Other conditions" the following sentence has been included:

 "- Trisequens tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine."

 

Section 6.1: "Blue tablets: Indigotin (E132)" now reads "Blue tablets: Indigo carmine (E132)"

Section 6.6: Heading changed to " Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product"                                     
 

 

Section 6.6: The following text has been added:
 

“No special requirement” has been removed and the following text added:

 

1. Set the day reminder

Turn the inner disc to set the wanted day of the week opposite the little plastic tab.

 

2. How to take the first tablet

Break the plastic tab and tip out the first tablet.

Phase 1: Blue tablets are taken for the first 12 days.

Phase 2: White tablets are taken for the next 10 days.

Phase 3: Red tablets are taken for the last 6 days.

 

3. Every day

Simply move the transparent dial clockwise one space as indicated by the arrow. Tip out the next tablet.
 
Section 7: Heading changed to: "NAME AND ADDRESS OF MARKETING AUTHORISATION HOLDER"
 
 
Section 9:  Has been updated to include renewal date   

Section 10. Heading changed to "DATE OF REVISION OF THE TEXT"
 
Section 10: Date been updated.

           

Updated on 16 July 2004 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 5 August 2003 SmPC

Reasons for updating

  • Change to section 6.1 - List of excipients
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.4 - Special precautions for storage
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 30 June 2003 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)