Public Assessment Report Decentralised Procedure

Federal Agency for Medicines and Health Products

Public Assessment Report

Decentralised Procedure

NOGEST 5 mg tablets Nomegestrol acetate

BE/H/137/01/DC

BE licence no: BE 325367

Applicant: Vandenbussche Farma Service bvba

Date: 06/10/2008

- 1 - This assessment report is published by the Federal Agency for Medicines and Health Products following Article 21 (3) and (4) of Directive 2001/83/EC, amended by Directive 2004/27/EC. The report comments on the registration dossier that was submitted to the Federal Agency for Medicines and Health Products and its fellow organisations in all concerned EU member states. It reflects the scientific conclusion reached by the Federal Agency for Medicines and Health Products and all concerned member states at the end of the evaluation process and provides a summary of the grounds for approval of a marketing authorisation. This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the latter category as the language in this report may be difficult for laymen to understand. This assessment report shall be updated by a following addendum whenever new information becomes available. To the best of the Federal Agency for Medicines and Health Products’ knowledge, this report does not contain any information that should not have been made available to the public. The MAH has checked this report for the absence of any confidential information.

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LAY SUMMARY

The Federal Agency for Medicines and Health Products granted Vandenbussche Farma bvba Marketing Authorisation for the medicinal product Nogest 5 mg tablets (BE 325367) on 6th October 2008. This pharmacy-only/prescription-only medicine is used for: In women before menopause: treatment of menstrual cycle disorders due to progesterone deficiency symptoms: - Menstrual cycle abnormalities: oligomenorrhea, polymenorrhea, spaniomenorrhea, amenorrhea. - Functional uterine bleeding: metrorrhagia, meno-metrorrhagia, menorrhagia, including those related to uterine fibroid. - Before or during menstruations: primary dysmenorrhea, premenstrual syndrome, breast tenderness. In post-menopausal women: treatment of menopause disorders, in combination with estrogens in non- hysterectomized women.

This is a decentralised application for Nogest 5mg tablets submitted under Article 10(1) of Directive 2001/83/EC (generic application).

Nomegestrol compensates the lack of progesterone, it’s affinity for the progesterone receptor is 2.5 fold greater than that of the natural hormone. If administered from the 5th to the 25th day of the menstrual cycle, it suppresses the ovulatory gonadotrophin peak, decreases the concentration of oestrogen in circulation, and prevents the secretion of progesterone.

The data submitted in support of the application for Nogest 5mg tablets raised no clinically significant safety concerns and it was therefore judged that the benefits of using these products outweigh the risks; hence a Marketing Authorisation has been granted.

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TABLE OF CONTENTS

Module 1: Information about the initial procedure Page 5

Module 2: Summary of Product Charcteristics Page 7

Module 3: Package Leaflets Page 16

Module 4: Labelling Page 21

Module 5: Scientific Discussion Page 24

1. Introduction 2. Quality aspects 3. Non-clinical aspects 4. Clinical aspects 5. Overall conclusion, benefit/risk assessment and recommendation

Module 6: Public Assessment Report – Update Page 27

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MODULE 1

INFORMATION ABOUT THE INITIAL PROCEDURE

1. Type of application

This application is being made according to Article 28 of Directive 2001/83/EC as amended, granted by the Belgian Health Authorities on 06-10-2008 (MA number: BE 325367).

This application concerns an abridged application, submitted according to Article 10 (1) Directive 2001/83/EC as amended. This type of application refers to information that is contained in the dossier of the authorisation of the reference product. A reference product is a medicinal product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological, pharmaceutical, pharmacological- toxicological and clinical data. This information is not fully available in the public domain. Authorisations for generic products are therefore linked to the ‘original’ authorised medicinal product, which is legally allowed once the data protection time of the dossier of the reference product has expired. For this kind of applications, it has to be demonstrated that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of the reference product. To this end a bio- equivalence study has to be submitted. A bioequivalence study is the widely accepted means of demonstrating that the therapeutic equivalence and the use of different excipients and different methods of manufacture has no influence on efficacy and safety. A generic product can be used instead of its innovator product. No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application.

This medicinal product Nogest 5mg tablets claims essential similarity with the innovator product Lutenyl 5mg tablets which has been registered in France by Laboratories Théramex since 1983. In addition reference is also made to Lutenyl 5mg tablets authorizations in the individual Member States (reference product). The reference product used for bioequivalence study is Lutenyl 5mg tablets, registered by Laboratories Théramex in France.

2. Active Substance

Nomegestrol acetate

3. Form tablets

4. Strength

5 mgr

5. MA Holder

MITHRA PHARMACEUTICALS S.A. Rue Saint Georges, 5 B- 4000 Liège Belgium

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6. RMS

The Reference Member State is Belgium.

7. CMS

The following member states were concerned: Luxembourg

8. Procedure-number

BE/H/037/01/DC

9. Timetable

Procedure Day 0: 12/10/2007 Procedure Day 70: 21/12/2007 Procedure Day 100: 20/01/2008 Procedure Day 105: 25/01/2008 Procedure Day 120: 16/05/2008 Procedure Day 180: 15/07/2008 Procedure Day 210: 14/08/2008

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MODULE 2

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

NOGEST 5 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg nomegestrol acetate. Excipients: lactose (as lactose monohydrate). For a full list of excipients see 6.1.

3. PHARMACEUTICAL FORM

Tablet White, oblong tablets with break-mark. The tablet can be divided into equal halves.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

In women before menopause: treatment of menstrual cycle disorders due to progesterone deficiency symptoms: - Menstrual cycle abnormalities: oligomenorrhea, polymenorrhea, spaniomenorrhea, amenorrhea. - Functional uterine bleeding: metrorrhagia, meno-metrorrhagia, menorrhagia, including those related to uterine fibroid. - Before or during menstruations: primary dysmenorrhea, premenstrual syndrome, breast tenderness.

In post-menopausal women: treatment of menopause disorders, in combination with estrogens in non- hysterectomized women.

4.2 Posology and method of administration

The usual posology is one tablet per day (5 mg/day).

- Women before menopause: the usual posology is a 10 days treatment, 1 tablet per day from 16th to 25th day inclusive, of the menstrual cycle.

- Post-menopausal women: the posology of NOGEST depends on the modalities of the combined estrogen therapy. With this therapy, the dosage of NOGEST is adjusted according the type of HRT scheme: “cyclic”: when the oestrogen is dosed cyclically with a treatment –free interval, usually 21 days on and 7 days off. The progestagen is usually added for 12-14 days of the cycle. “continuous sequential”: the oestrogen is dosed continuously. The progestagen is usually

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added for 12-14 days (or more) of every 28 day cycle, in a sequential manner. “continuous combined”: the oestrogen and the progestagen are given every day without interruption.

Dosage and duration of treatment may be adjusted according to severity of symptoms or clinical response.

The tablets should be preferably administered under fasting conditions and not immediately after a meal.

4.3 Contra-indications

- Known hypersensitivity to the active substances or to any of the excipients. - Arterial thromboembolism present or in history (myocardial infarction, cerebrovascular disorder). - Venous thromboembolism present or in history (deep venous thrombosis, pulmonary embolism). - Severe hepatic disorders. - Undiagnosed vaginal bleeding. - Suspected or confirmed breast cancer.

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

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

In the case of uterine haemorrhage, do not use the product until a diagnosis has been confirmed that excludes an organic cause.

Conditions which need supervision • If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Nogest, in particular: - Leiomyoma (uterine fibroids) or endometriosis - A history of, or risk factors for, thromboembolic disorders (see below) - Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer - Hypertension - Liver disorders (e.g. liver adenoma) - Diabetes mellitus with or without vascular involvement - Cholelithiasis - Migraine or (severe) headache - Systemic lupus erythematosus

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- A history of endometrial hyperplasia (see below) - Epilepsy - Asthma - Otosclerosis

The use of NOGEST should be stopped immediately in the case of ocular disorders (partial or total loss of sight, diplopia, vascular lesions of the retina), venous thromboembolic or thrombotic accidents in peripheral, pulmonary or cerebral vessels, cephalgia of particular intensity.

NOGEST should be used with care in cases of hypertension, diabetes, phlebitis, and porphyria.

Reasons for immediate withdrawal of therapy: Therapy should be discontinued in case a contra-indication is discovered and in the following situations: - Jaundice or deterioration in liver function - Significant increase in blood pressure - New onset of migraine-type headache - Pregnancy Endometrial hyperplasia • The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk. • Break-through bleeding and spotting may occur during the first months of treatment. If break- through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy. Breast cancer A randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS) have reported an increased risk of breast cancer in women taking oestrogens, oestrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, and excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment. In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration. In the WHI study, the continuous combined conjugated equine 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-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer. Venous thromboembolism • HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two-to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate=4) per 1000 women aged 50-59

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years and between 5 and 15 (best estimate=9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later. • Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI>30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE. • Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. • The risk of VTE may be temporalily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised. • If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g, painful swelling of a leg, sudden pain in the chest, dyspnea). Coronary artery disease (CAD) • There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens 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 finding also extend to other HRT products. Stroke • One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated 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 estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products. Ovarian cancer • Long-term (at least 5-10 years) use of 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 HRTs confers to a different risk than oestrogen-only products. Other conditions • Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in X is increased. • “Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases

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of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.” • “Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex- hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).” • There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products. NOGEST contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interactions with other medicinal product and other forms of interaction

The metabolism of nomegestrol acetate may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin, primidone), griseofulvin, barbiturates, rifampicin, rifabutin, and preparations containing Hypericum perforatum. Clinically, an increased metabolism of nomegestrol acetate may lead to decreased effect and changes in the uterine bleeding profile.

4.6 Pregnancy and lactation

Pregnancy NOGEST is not indicated during pregnancy. If pregnancy occurs during medication with NOGEST, treatment should be withdrawn immediately. There are no adequate data from the use of nomegestrol actetate in pregnant women. However, epidemiologic studies relevant to inadvertent foetal exposure to progestogens indicate no teratogenic or foetotoxic effects.

Lactation Small amounts of steroid materials appear in the milk. Therefore, NOGEST is not recommended in breastfeeeding women.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

There is a good general and digestive tolerance without major undesirable effects : hormonal, vascular, hepatic or metabolic. Occasionaly, changes in menstruation, amenorrhea and intercurrent haemorrhage may occur. Some of the adverse drug reactions listed below may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.

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The following undesirable effects have been reported:

Gastrointestinal disorders - Exceptional cases : gastrointestinal disorders.

Skin and subcutaneous tissue disorders - Itching - Rarely : Cutaneous hypersensitivity reaction, increased hair growth Vascular disorders - Worsening of venous insufficiency in the lower limbs - Exceptional cases : Venous thromboembolism General disorders and administration site conditions: - Exceptional cases : Weight increase, insomnia Hepato-biliary disorders - Onset of cholestatic jaundice Reproduction system and breast disorders: - Occasionally : Change in menstruation, irregular bleeding, amenorrhoea. Breast cancer According to evidence from a large number of epidemiological studies and one randomised placebo- controlled trial, the Women’s Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users. For 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 progestagen 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-progestagen 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- progestagen combined HRT (CEE + MPA) in all users compared with placebo. The absolute risks calculated from the MWS and the WHI trial are presented below: The MWS has estimated, from the known average incidence of breast cancer in developed countries, that: 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 progestagen combined HRT, • between 5 and 7 (best estimate = 6) for 5 years’ use

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• 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-progestagen combined HRT (CEE + MPA) per 10,000 women years. According to calculations from the trial data, it is estimated that: For 1000 women in the placebo group, • about 16 cases of invasive breast cancer would be diagnosed in 5 years. For 1000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be • between 0 and 9 (best estimate = 4) for 5 years’ use. The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).’ Endometrial cancer In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed 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 progestagen to oestrogen-only therapy greatly reduces this increased risk. Other adverse reactions have been reported in association with oestrogen/progestagen treatment: - Oestrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer. - Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use. - Myocardial infarction and stroke - Gall bladder disease. - Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura. - Probable dementia (see section 4.4)

4.9 Overdose

No case of harmful effects has been reported during clinical trials where the highest dose administered to patients was up to 10 times the recommended dose during several weeks.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Genito urinary system and sex hormones / Pregnadien derivatives. ATC code: G03DB04 Nomegestrol is a synthetic, potent, orally active progestogen derived from active 19-nor-progesterone. Administration of 5 mg per day of Nomegestrol acetate from 5th to 24th day suppresses the ovulatory pic of gonadotropines, decrease the level of circulating oestrogens and blocks the release of

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In various biopharmacological surveys nomegestrol acetate has not shown any androgenous, anabolic, estrogenic, glucocorticoid or mineralocorticoid activity. Interference with glucidic metabolism and hydroelectrolytic balance has not been shown. Cardiovascular, hepatic or metabolic tolerability is excellent.

Progestagen: As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces the oestrogen- induced risk of endometrial hyperplasia in non-hysterectomised women.

5.2 Pharmacokinetic properties

Administration of a single dose has been followed by rapid absorption with plasma peak 2 hours after taking the product.

The half-life is about 40 hours. Plasma protein binding of nomegestrol acetate is 97.7 + 0.1% similarly to progesterone (97.2 to 97.6%) . Nomegestrol acetate bind neither to SHBG nor to CBG. Good availability after oral administration and a long half-life enable 1 single daily administration.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeat dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate, Microcrystalline cellulose, Silica colloidal, Glycerol palmitostearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

No special storage conditions.

6.5 Nature and contents of container

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Blister: PVC/aluminium. Pack sizes: 3 x 10 tablets, 3 x 14 tablets, 6 x 10 tablets, 6 x 14 tablets, 9 x 10 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

MITHRA PHARMACEUTICALS S.A. Rue Saint Georges, 5 B- 4000 Liège Belgium

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<{DD/MM/YYYY}>

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

<{MM/YYYY}>

<[To be completed nationally]>

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MODULE 3

PACKAGE LEAFLET: INFORMATION FOR THE USER

NOGEST 5 mg tablets nomegestrol acetate

Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet: 1. What NOGEST is and what it is used for 2. Before you use NOGEST 3. How to use NOGEST 4. Possible side effects 5. How to store NOGEST 6. Further information

1. WHAT NOST IS AND WHAT IT IS USED FOR

NOGEST belongs to the group of medicines called “progestogen”. The action of this medicine is located on female sex organs (i.e. breast and sexual organs), such as the progesterone, which is a natural hormone produced in women’s body. NOGEST is used: - In women before menopause, for the treatment of menstrual cycle disorders caused by the absence or low secretion of progesterone. These troubles of the menstrual cycle can be: - Menstrual cycle length abnormalities, - Bleeding abnormalities during or outside menstruation, - Painful menstruation, - Troubles before menstruation such as nervousness or irritability (premenstrual syndrome), - Breast tenderness. - In post menopausal women, for the treatment of menopause disorders in addition with a treatment containing estrogen in non-hysterectomized women.

2. BEFORE YOU USE NOGEST

Do not use NOGEST - If you are allergic (hypersensitive) to the active substance, or any of the other ingredients of this medicine (refer to section “6.Further information”).

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- If you have (or if you have had) a blood clot in a blood vessel of the leg (phlebitis), lung (embolus), heart (myocardial infarction), brain (cerebrovascular disorder) or other organs. - If you have a liver disease and your liver is still not functioning normally, or if you have a liver cancer. - If you have any unexplained bleeding from the vagina. - If you have (or if you have had) breast cancer or if your doctor thinks you are having breast cancer. - If you are pregnant. - If you are breast-feeding.

Take special care with NOGEST

In some situations you need to take special care while using NOGEST or any other sex hormones. Your doctor will regularly check you if necessary. You must inform your doctor before starting to use NOST: - If you have genital bleedings that are not explained yet. - If you have (or have had) a heart attack or stroke. - If you have high blood sugar (diabetes). - If you have high blood pressure. - If you have an accumulation of compounds derived of iron in the liver (porphyria).

If you have (or have had) the following conditions, you must inform your doctor :

- Leiomyoma (uterine fibroids) or endometriosis - A history of, or risk factors for, thromboembolic disorders (see below) - Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer - Hypertension - Liver disorders (e.g. liver adenoma) - Diabetes mellitus with or without vascular involvement - Cholelithiasis - Migraine or (severe) headache - Systemic lupus erythematosus. - A history of endometrial hyperplasia (see below) - Epilepsy - Asthma - Otosclerosis

If one of these problems appears or gets serious while using NOGEST, you should contact your doctor.

NOGEST and cancer Breast cancer has been observed slightly more often in menopausal women who use this type of treatment (also called hormone replacement therapy). However it is not known whether this type of treatment caused these observed breast cancers. For safety reason, you should regularly check your breasts and you should contact your doctor if you feel any lump.

Using other medicines Some medicines can make NOGEST less effective and particularly: - medicines used to treat epilepsy (e.g. carbamazepine, phenobarbital, phenytoin, primidone, barbiturates), - medicines used to treat tuberculosis (e.g. rifampicin), - medicines used to treat other infectious diseases (e.g. griseofulvin, rifabutin), - and the herbal remedy St. John’s wort used to treat depression.

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If you want to use one of these medicines, you should tell your doctor who will adapt your treatment if necessary.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding You should not use NOGEST if you are pregnant. You should not use NOGEST if you are breastfeeding.

Ask your doctor for advice before taking any medicine.

Driving and using machines There is no information suggesting that use of NOGEST affects driving or use of machines.

Important information about some of the ingredients of NOGEST NOGEST contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medical product.

3. HOW TO USE NOGEST

Dosage Always use NOGEST exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The usual posology is one tablet per day (5 mg/day). The tablets should be preferably administered under fasting conditions and not immediately after a meal.

Frequency of administration

- Women before menopause: the usual dosage is 1 tablet per day during 10 days (from day 16 of the menstrual cycle to day 25 inclusive). - Post-menopausal women: NOGEST is used in addition to a treatment containing estrogen. In cyclic schemes, when the oestrogen is dosed cyclically with a treatment-free interval, usually 21 days on and 7 days off. The progestagen is usually added for 12-14 days of the cycle. In continuous sequential, the oestrogen is dosed continuously and the progestagen is usually added for 12-14 (or more) of every 28 day cycle, in a sequential manner. In continuous combined, the oestrogen and the progestagen are given every day without interruption.

Duration of treatment Your doctor will decide the duration of treatment. Your doctor will adjust the dosage and the duration of treatment according to severity of the diseases and the effect of NOGEST on your body.

If you use more NOGEST than you should Contact your doctor or pharmacist.

If you forget to use NOGEST If you forget to take a dose, take it as soon as you remember. However if it is within twelve hours of the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take a double dose to make up for a forgotten dose.

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If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, NOGEST can cause side effects, although not everybody gets them.

You should stop taking NOGEST immediately and contact your doctor if you have:

- A pain in the calf. It can be caused by the forming of blood clots in your leg (phlebitis). - Breathing difficulty. This can be caused by the forming of blood clots in your lungs (pulmonary embolism). - Forming of blood clots in your brain (cerebrovascular accident), heart or eyes. - Headache of particular intensity. - Ocular disorders (double vision, partial or total loss of sight…). The following side effects may occur. If one of these side effects occurs, do not hesitate to contact your doctor or pharmacist who will tell you what to do.

Effects on the sexual organs: occasionally: change in menstruation, irregular bleeding or absence of menstruation (amenorrhoea). Effects on the stomach and bowel : Gastrointestinal disorders can occur in exceptional cases. Effets on the liver and biliary tract: yellowing of the skin or whites of the eyes caused by liver or blood problems (cholestatic jaundice). Effects on the skin: itching, cutaneous hypersensitivity reaction (e.g. itching, pimples and swelling) in rare cases and increased hair growth in exceptional cases. Effects on the blood vessels: worsening of the blood circulation in the legs (venous insufficiency in the lower limbs) and forming of a blood clot in a vein (venous thromboembolism) in exceptional cases.

General effects: in exceptional cases: weight increase or insomnia.

You should also see “before you use Nogest, Nogest and cancer”.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE NOGEST

Keep the medicine out of the reach and sight of children.

No special storage conditions.

Do not use NOGEST after the expiry date which is stated on the carton and blister after ‘EXP’. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

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6. FURTHER INFORMATION

What NOGEST contains

- The active substance is nomegestrol acetate (5 mg). - The other ingredients are: lactose monohydrate, microcrystalline cellulose, silica colloidal, glycerol palmitostearate.

What NOGEST looks like and contents of the pack

NOGEST is a white, long tablet with a breakable-mark on the two sides to cut the tablet in two parts if necessary. The pills are supplied in a blister strip. Each strip contains 10 or 14 tablets. The blister strips are supplied in a carton box. Each box contains 3 (strip of 10 or 14 tablets), 6 (strip of 10 or 14 tablets) or 9 (strip of 10 tablets) blister strips.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: MITHRA PHARMACEUTICALS S.A. Rue Saint Georges, 5 B- 4000 Liège Belgium

Manufacturer: HAUPT PHARMA Münster GmbH Schleebrüggenkamp 15, D-48159 Münster Germany

This medicinal product is authorised in the Member States of the EEA under the following names: Belgium, Luxemburg : Nogest 5 mg tablets

This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

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MODULE 4

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING Outer box

1. NAME OF THE MEDICINAL PRODUCT

NOGEST 5 mg tablets nomegestrol acetate

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Composition: Nomegestrol acetate 5 mg.

3. LIST OF EXCIPIENTS

Contains lactose, see leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

3 x 10 tablets 3 x 14 tablets 6 x 10 tablets 6 x 14 tablets 9 x 10 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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No special storage conditions.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

MITHRA PHARMACEUTICALS S.A. Rue Saint Georges, 5 B- 4000 Liège Belgium

12. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

13. BATCH NUMBER

BATCH

14. GENERAL CLASSIFICATION FOR SUPPLY

<[To be completed nationally]>

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

NOGEST 5 mg

***

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Blister (10 tablets, 14 tablets)

1. NAME OF THE MEDICINAL PRODUCT

NOGEST 5 mg tablets nomegestrol acetate

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MITHRA PHARMACEUTICALS S.A.

3. EXPIRY DATE

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EXP

4. BATCH NUMBER

BATCH

5. OTHER

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MODULE 5

SCIENTIFIC DISCUSSION DURING INITIAL PROCEDURE

This module reflects the scientific discussion for the approval of Nogest 5mg tablets. The procedure was finalised at 14th august 2008. For information on changes after this date please refer to the module 6.

I. INTRODUCTION This Marketing Authorisation Application (MAA) is submitted in accordance with article 10(1) of Directive 2001/83/EC (generic application), using the decentralised procedure BE/H/0137/01/DC. Belgium is the Reference Member State and Luxembourg is the Concerned Member State.

Nomegestrol acetate, described for the first time in 1983, is a synthetic 19-norprogesterone derivative that binds to the androgen and progesterone receptors and has moderate antiestrogenic and anti- androgenic activity. It has no anabolic, adrenocorticalic, or anti- inflammatory activity and did not interfere with the metabolism of carbohydrate, water and electrolytes. It is used in the treatment of menstrual disorders due to insufficiency or lack of progesterone secretion in women before menopause. It is also used in the treatment of post-menopausal disorders in association with oestrogens.

The EU reference product referred to is Lutenyl 5 mg tablets, Laboratories Théramex, France. This medicinal product is already authorised since 1983. The reference product used in the bioequivalence studies is Lutenyl 5 mg tablets, Laboratories Théramex, France.

The MAH declares that an EU-RMP is not required.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. A confirmation should be given by the qualified person of the finished product manufacturer that the active substance is still produced under GMP conditions.

II. QUALITY ASPECTS

I.1 Introduction Nogest 5 mg scored tablets are white, oblong tablets with break- mark on the two sides. The tablets are packed in PVC-Aluminium push-through-blister with an increased vapour barrier. Pack sizes of one or three blister- trays containing 10 tablets are packed into a folding carton with the patient information leaflet.

I.2 Drug Substance The active substance, Nomegestrol Acetate, is described in the Ph.Eur. Nomegestrol Acetate is the subject of an ASMF procedure (Newchem SpA). The description of the manufacturing process is sufficiently detailed to allow a reasonable evaluation of potential impurities arising from the synthesis. The controls of the starting materials and the in- process controls are sufficient to warrant the quality of the Nomegestrol Acetate. The proposed specifications are suitable to control its quality and comply with the Ph. Eur. monograph for Nomegestrol Acetate and with the Ph. Eur. general chapter 5.10 “Control of Impurities in Substances for Pharmaceutical Use”.

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Based on the available stability results, a re-test period of 12 months is acceptable.

I.3 Medicinal Product The formulation of Nogest has been developed based on the qualitative and quantitative composition of the reference product. The pharmaceutical development of the product is appropriately documented. The manufacturing process is adequately described and the validation data demonstrate its consistency. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis data are provided for four commercial- scale batches. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. Considering the presented stability results, a shelf life of 24 months, without special storage conditions, is justified.

III. NON-CLINICAL ASPECTS

Pharmacodynamic, pharmacokinetic and toxicological properties of nomegestrol acetate are well known. As nomegestrol acetate is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.

IV. CLINICAL ASPECTS

I.4 Introduction The application for marketing authorisation of the generic Nogest is based on a bioequivalence study demonstrating bioequivalence of the test product with the approved reference product Lutenyl 5 mg.

I.5 Pharmacokinetics Bioequivalence studies were conducted according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence, CPMP/EWP/QWP/1401/98. The study design, sample size, analytical and statistical methods are appropriate. The 90% confidence intervals of the ratios of geometric means are well in the acceptance range of 80-125% for the primary parameters AUC and Cmax. Nogest 5 mg tablets can therefore be considered as bioequivalent to Lutenyl® 5 mg tablets with respect to rate and extent of absorption.

I.6 Pharmacodynamics N/A

I.7 Clinical efficacy and safety No new clinical studies have been performed using the study drug and the clinical assessment is based on studies concerning the reference drug, Lutenyl.

- Improvement of quality of life induced by estrogen replacement therapy in post menopausal women remains unchanged during cyclical administration of nomegestrol acetate - During the menopause transition, cyclic nomegestrol acetate administration may contribute to reduce negative modification of body composition (increase in the resting metabolic rate – decrease in the fat mass). - It has been shown that 1.5 mg estradiol is effective in reducing bone turnover in postmenopausal women and that the combination of 1.5 mg estradiol and 3.75 mg nomegestrol acetate has no deleterious effect on bone remodelling

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I.8 Discussion on the clinical aspects

Comparative dissolution profiles are provided between the test product Nogest 5mg tablets and the reference product Lutenyl 5 mg tablets; these profiles what are considered statistically similar.

V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

An adequate review of published non-clinical and clinical data and the bioequivalence has been shown. The submitted quality information on the proposed product is acceptable. No major deficits were observed.

Indications and posology are similar to that of the reference drug, Lutenyl 5mg.

The following commitments have been made during the procedure: ƒ To submit a type II variation in order to update the SPC of Nogest as soon as the SPC of the originator product is updated. ƒ To subcontract an external fully qualified consultant with high expertise in Pharmacovigilance. ƒ To request for an Audit by the external consultant of the pharmacovigilance quality system in place. ƒ To update the Pharmacovigilance Quality System: edition of new procedure and update of existing procedure according to the result of the audit, the part 3.c of the Detailed Description of the Pharmacovigilance System and the current legislation. ƒ To assure regular training by external qualified structure of the QPPV and his back-up in field of Eudravigilance, MedDRA, CIOM’s.

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MODULE 6

Public Assessment Report – Update

Scope Procedure number Type of modification Date of start of Date of end Approval/ Assessment the procedure of non report procedure approval attached Type II analytical BE/H/137/01/II/03 Update of the ASMF of Nomegestrol 23/10/2009 04/03/2010 Approval N variation acetate from Newchem (IT). Main changes are linked to the manufacturing process and the GC method used to check residual solvents.

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