Trisequens

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

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

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

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

·        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