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MHRA PAR; DESOREX 75 MICROGRAMS FILM-COATED TABLETS, PL 15764/0044 1 Public Assessment Report Decentralised Procedure Desorex 75 micrograms film-coated tablets PL 15764/0044 UK/H/4261/01/DC Strandhaven Ltd T/A Somex Pharma

Public Assessment Report Decentralised … contrast to the combined pill, Desorex can be used by women who do not tolerate oestrogens and by women who are breast feeding. A disadvantage

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Page 1: Public Assessment Report Decentralised … contrast to the combined pill, Desorex can be used by women who do not tolerate oestrogens and by women who are breast feeding. A disadvantage

MHRA PAR; DESOREX 75 MICROGRAMS FILM-COATED TABLETS, PL 15764/0044 1

Public Assessment Report

Decentralised Procedure

Desorex 75 micrograms film-coated tablets

PL 15764/0044

UK/H/4261/01/DC

Strandhaven Ltd T/A Somex Pharma

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Lay summary

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Strandhaven Ltd T/A Somex Pharma a Marketing Authorisation (licence) for the medicinal product Desorex 75 micrograms film-coated tablets (product licence number: PL 15764/0044) on 9 November 2011. This medicine is available on prescription only. Desorex is used to prevent pregnancy. It contains a small amount of one type of female sex hormone, the progestogen desogestrel. For this reason, Desorex is called a progestogen-only pill (POP), or a mini-pill. Unlike the combined pill, the mini-pill does not contain an oestrogen hormone, only a progestogen. Most mini-pills work primarily by preventing the sperm cells from entering the womb. They do not always prevent the egg cell from ripening, which is the primary action of combined pills. Desorex is distinct from other mini-pills in having a dose that in most cases is high enough to prevent the egg cell from ripening. As a result, Desorex provides high contraceptive efficacy. In contrast to the combined pill, Desorex can be used by women who do not tolerate oestrogens and by women who are breast feeding. A disadvantage is that vaginal bleeding may occur at irregular intervals during the use of Desorex. The data submitted in support of this application for Desorex 75 micrograms film-coated tablets raised no clinically significant safety concerns and it was, therefore, judged that the benefits of using this product outweigh the risks; hence a Marketing Authorisation has been granted.

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TABLE OF CONTENTS

Module 1: Information about Decentralised Procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 15 Module 4: Labelling Page 20 Module 5: Scientific Discussion Page 22 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions

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Module 1

Information about Decentralised Procedure

Name of the product in the Reference Member State

Desorex 75 micrograms film-coated tablets

Type of application Generic (Article 10.1)

Name of the active substance (INN)

Desogestrel

Pharmacotherapeutic classification (ATC code)

Hormonal contraceptives for systemic use (G03AC09)

Pharmaceutical form and strength

Film-coated tablets, 75 micrograms

Reference number for the Decentralised Procedure

UK/H/4261/01/DC

Reference Member State

United Kingdom

Member States concerned

Cyprus

Start date of Decentralised Procedure 19 May 2010

End date of Decentralised Procedure 12 October 2011

Marketing Authorisation number PL 15764/0044

Name and address of the authorisation holder

Strandhaven Ltd T/A Somex Pharma High Road Ilford Essex IG3 8BS United Kingdom

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Module 2

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT Desorex 75 micrograms film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 micrograms desogestrel. Excipient: Each film-coated tablet contains 54.35 mg lactose monohydrate. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet. White to off white, circular, biconvex tablets, 5.5mm in diameter, without embossing.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Oral contraception. 4.2 Posology and method of administration

Method of administration Tablets must be taken every day at about the same time with a small amount of liquid so that the interval between two tablets is always 24 hours. The first tablet should be taken on the first day of menstrual bleeding. Thereafter one tablet each day is to be taken continuously, without taking any notice on possible bleeding. A new blister is started directly the day after the previous one. How to start Desorex No preceding hormonal contraceptive use (in the past month) Tablet-taking has to start on day 1 of the woman’s natural cycle (day 1 is the first day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the first cycle a barrier method is recommended for the first 7 days of tablet-taking. Following first-trimester abortion After first-trimester abortion it is recommended Desorex is started immediately. In which case there is no need to use an additional method of contraception. Following delivery, preterm delivery or second-trimester abortion

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Contraceptive treatment with Desorex after delivery can be initiated before the menstruations have returned. If more than 21 days have elapsed after delivery, pregnancy ought to be ruled out and an additional method of contraception should be used for the first week. For additional information on breastfeeding women. (see section 4.6). How to start Desorex when changing from other contraceptive methods Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch). The woman should start Desorex preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC or on the day of removal of her vaginal ring or transdermal patch. In these cases, the use of an additional contraceptive is not necessary. Not all contraceptive methods may be available in all EU countries. The woman may also start at the latest on the day following the usual tablet-free, patch-free, ring-free, or placebo tablet interval of her previous combined hormonal contraceptive, but during the first 7 days of tablet-taking an additional barrier method is recommended. Changing from a progestogen-only-method (minipill, injection, implant or from a progestogen-releasing intrauterine system [IUS]) The woman may switch any day from the minipill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due). Additional contraceptive method is not necessary. Management of missed tablet Contraceptive protection may be reduced if more than 36 hours have elapsed between two tablets. If the user is less than 12 hours late in taking any tablet, the missed tablet should be taken as soon as it is remembered and the next tablet should be taken at the usual time. If she is more than 12 hours late, she should use an additional method of contraception for the next 7 days. If tablets were missed in the first week and intercourse took place in the week before the tablets were missed, the possibility of a pregnancy should be considered. Advice in case of gastrointestinal disturbances In case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, absorption may not be complete. In such an event, the advice concerning missed tablets, as given in this section is applicable.

Treatment surveillance Before prescription, a thorough case history should be taken and a thorough gynaecological examination is recommended to exclude pregnancy. Bleeding disturbances, such as oligomenorrhoea and amenorrhoea should be investigated before prescription. The interval between check-ups depends on the circumstances in each individual case. If the prescribed product may conceivably influence latent or

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manifest disease (see section 4.4), the control examinations should be timed accordingly. Despite the fact that Desorex is taken regularly, bleeding disturbances may occur. If bleeding is very frequent and irregular, another contraceptive method should be considered. If the symptoms persist, an organic cause should be ruled out. Management of amenorrhoea during treatment depends on whether or not the tablets have been taken in accordance with the instructions and may include a pregnancy test. The treatment should be stopped if a pregnancy occurs. Women should be advised that Desorex does not protect against HIV (AIDS) and other sexually transmitted diseases. Paediatric population There is no relevant indication for use of Desorex in children.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients. - Known or suspected pregnancy. - Active venous thromboembolic disorder. - Presence or history of severe hepatic disease as long as liver function

values have not returned to normal. - Known or suspected sex-steroid sensitive malignancies. - Undiagnosed vaginal bleeding.

4.4 Special warnings and precautions for use

If any of the conditions/risk factors mentioned below is present, the benefits of progestogen use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start with Desorex. In the event of aggravation, exacerbation, or first appearance of any of these conditions, the woman should contact her physician. The physician should then decide on whether the use of Desorex should be discontinued. The risk for breast cancer increases in general with increasing age. During use of combined oral contraceptives (COCs) the risk of having breast cancer diagnosed is slightly increased. This increased risk disappears gradually within 10 years after discontinuation of COC use and is not related to the duration of use, but to the age of the woman when using the COC. The expected number of cases diagnosed per 10,000 women who use COCs (up to 10 years after stopping) relative to never users over the same period has been calculated for the respective age groups and is presented in the table below. Age Group Expected

Cases COC-Expected cases COC-

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users non-users 16-19 years 4.5 4 20-24 years 17.5 16 25-29 years 48.7 44 30-34 years 110 100 35-39 yeas 180 160 40-44 years 260 230 The risk in users of progestogen-only contraceptives (POC), such as Desorex, is possibly of similar magnitude as that associated with COCs. However, for POCs the evidence is less conclusive. Compared to the risk of getting breast cancer ever in life, the increased risk associated with COCs is low. The cases of breast cancer diagnosed in COC users tend to be less advanced than in those who have not used COCs. The increased risk in COC users may be due to an earlier diagnosis, biological effects of the pill or a combination of both. Since a biological effect cannot be excluded, an individual benefit/risk assessment should be made in women with pre-existing breast cancer and in women in whom breast cancer is diagnosed while using desogestrel-only pill.

Since a biological effect of progestogens on liver cancer cannot be excluded an individual benefit/risk assessment should be made in women with liver cancer. When acute or chronic disturbances of liver function occur the woman should be referred to a specialist for examination and advice. Epidemiological investigations have associated the use of COCs with an increased incidence of venous thromboembolism (VTE, deep venous thrombosis and pulmonary embolism). Although the clinical relevance of this finding for desogestrel used as a contraceptive in the absence of an oestrogenic component is unknown, Desorex should be discontinued in the event of a thrombosis. Discontinuation of Desorex should also be considered in case of long-term immobilisation due to surgery or illness. Women with a history of thrombo-embolic disorders should be made aware of the possibility of a recurrence. Although progestogens may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using progestogen-only pills. However, diabetic patients should be carefully observed during the first months of use. If a sustained hypertension develops during the use of Desorex, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, the discontinuation of Desorex should be considered. Treatment with Desorex leads to decreased oestradiol serum levels, to a level corresponding with the early follicular phase. It is as yet unknown whether the decrease has any clinically relevant effect on bone mineral density. The protection with traditional progestogen-only pills against ectopic pregnancies is not as good as with combined oral contraceptives, which has been associated with the frequent occurrence of ovulations during the use of

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progestogen-only pills. Despite the fact that Desorex consistently inhibits ovulation, ectopic pregnancy should be taken into account in the differential diagnosis if the woman gets amenorrhoea or abdominal pain. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking Desorex. The following conditions have been reported both during pregnancy and during sex steroid use, but an association with the use of progestogens has not been established: - jaundice and/or pruritus related to cholestasis; - gallstone formation; porphyria; - systemic lupus erythematosus; - haemolytic uraemic syndrome; - Sydenham’s chorea; - herpes gestationis; - otosclerosis-related hearing loss; - (hereditary) angioedema. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Maturation of follicles Follicular development occurs during the use of all low-dose hormonal contraceptives. The follicles may occasionally grow to be larger than their normal size in the menstrual cycle. Generally, the enlarged follicles (functional cysts) disappear spontaneously. They are often asymptomatic but in some cases mild abdominal pain may occur. Surgical intervention is rarely required.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions between hormonal contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature (mainly with combined contraceptives but occasionally also with progestogen-only contraceptives). Hepatic metabolism: Interactions can occur with medicinal products that induce microsomal enzymes, which can result in increased clearance of sex hormones (such as, hydantoins (e.g. phenytoin), barbiturates (e.g. phenobarbital), primidone, carbamazepine, rifampicin, and possibly also for oxcarbazepine, topiramate, rifabutin, felbamate, ritonavir, nelfinavir, griseofulvin and products containing St. John’s wort (Hypericum perforatum)). Maximal enzyme induction is not seen for 2-3 weeks, but may then be sustained for at least 4 weeks after the cessation of drug therapy. Women on treatment with any of these medicinal products should temporarily use a barrier method in addition to Desorex. With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. For women on long-

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term therapy with hepatic enzyme inducers a non-hormonal method contraception should be considered. During treatment with medical charcoal, the absorption of the steroid in the tablet may be reduced and thereby the contraceptive efficacy. Under these circumstances, the advice as given for missed tablets in section 4.2. is applicable. Hormonal contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporine) or decrease. Note: The prescribing information of concomitant medications should be consulted to identify potential interactions. Laboratory tests Data obtained with COCs have shown that contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, serum levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. The changes generally remain within the normal range. To what extent this also applies to progestogen-only contraceptives is not known.

4.6 Fertility, pregnancy and lactation

Desorex is contraindicated (see section 4.3) in pregnancy. Animal studies have shown that very high doses of progestogenic substances might cause masculinisation of female fetuses. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs before pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy. Pharmacovigilance data collected with various desogestrel-containing COCs also do not indicate an increased risk. Desogestrel does not influence the production or the quality (protein, lactose, or fat concentration) of breast milk. However, small amounts of etonogestrel are excreted in the breast milk. As a result, 0.01 - 0.05 micrograms etonogestrel per kg body weight per day might be ingested by the child (based on an estimated milk ingestion of 150 millilitre per kg body weight per day). Limited long-term follow-up data are available on children, whose mothers started using desogestrel during the 4th to 8th weeks post-partum. They were breast-fed for 7 months and followed up to 1.5 years (n=32) or to 2.5 years (n=14) of age. Evaluation of growth and physical and psychomotor development did not indicate any differences in comparison to nursing infants, whose mother used a copper-IUD. Based on the available data, Desorex may

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be used during lactation. The development and growth of a nursing infant, whose mother uses Desorex, should, however, be carefully observed.

4.7 Effects on ability to drive and use machines

Desorex has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The most commonly reported undesirable effect in the clinical trials is bleeding irregularity. Some kind of bleeding irregularity has been reported in up to 50% of women using desogestrel. Since desogestrel causes ovulation inhibition close to 100%, in contrast to other progestogen-only-pills, irregular bleeding is more common than with other progestogen-only pills. In 20 -30% of the women, bleeding may become more frequent, whereas in another 20% bleeding may become less frequent or totally absent. Vaginal bleeding may also be of longer duration. After a couple of months of treatment, bleedings tend to become less frequent. Information, counselling and a bleeding diary can improve the woman’s acceptance of the bleeding pattern. The most commonly reported other undesirable effects in the clinical trials with desogestrel (> 2.5%) were acne, mood changes, breast pain, nausea and weight increase. The undesirable effects mentioned in the table below have been judged, by the investigators, as having an established, probable or possible link to the treatment. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), Not known (cannot be estimated from the available data).

Frequency of adverse reactions System Organ Classes Common Uncommon Rare Infections and infestations

Vaginal infection

Psychiatric disorders

Mood altered, libido decreased

Nervous system disorders

Headache

Eye disorders Contact lens intolerance

Gastrointestinal disorders

Nausea Vomiting

Skin and subcutaneous tissue disorders

Acne Alopecia Rash, urticaria, Erythema nodosum

Reproductive system and

Breast pain, menstruation

Dysmenorrhoea, ovarian cyst

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breast disorders

irregular, amenorrhoea

General disorders and administration site conditions

Fatigue

Investigations Weight increased

Breast discharge may occur during use of desogestrel. On rare occasions, ectopic pregnancies have been reported (see section 4.4). In women using (combined) oral contraceptives a number of (serious) undesirable effects have been reported. These include venous thromboembolic disorders, arterial thromboembolic disorders, hormone-dependent tumours (e.g. liver tumours, breast cancer) and chloasma, some of which are discussed in more detail in section 4.4.

4.9 Overdose

There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case are nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: hormonal contraceptives for systemic use, ATC code: G03AC09. Desorex is a progestogen-only pill, which contains the progestogen desogestrel. Like other progestogen-only pills, Desorex is best suited for use during breast-feeding and for women who may not or do not want to use oestrogens. In contrast to traditional progestogen-only pills, the contraceptive effect of Desogestrel is achieved primarily by inhibition of ovulation. Other effects include increased viscosity of the cervical mucus. When studied for 2 cycles, using a definition of ovulation as a progesterone level greater than 16 nmol/L for 5 consecutive days, the ovulation incidence was found to be 1% (1/103) with a 95% confidence interval of 0.02% - 5.29% in the ITT group (user and method failures). Ovulation inhibition was achieved from the first cycle of use. In this study, when desogestrel was discontinued after 2 cycles (56 continuous days) ovulation occurred on average after 17 days (range 7-30 days). In a comparative efficacy trial (which allowed a maximum time of 3 hours for missed pills), the overall ITT Pearl-Index found for desogestrel was 0.4 (95% confidence interval 0.09 - 1.20), compared to 1.6 (95% confidence interval 0.42 - 3.96) for 30 μg levonorgestrel.

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The Pearl-Index for Desogestrel is comparable to the one historically found for COCs in the general COC-using population. Treatment with Desogestrel leads to decreased estradiol levels, to a level corresponding to the early follicular phase. No clinically relevant effects on carbohydrate metabolism, lipid metabolism and haemostasis have been observed.

5.2 Pharmacokinetic properties

Absorption After oral dosing of desogestrel (DSG) is rapidly absorbed and converted into etonogestrel (ENG). Under steady-state conditions, peak serum levels are reached 1.8 hours after tablet-intake and the absolute bioavailability of ENG is approximately 70%. Distribution ENG is 95.5-99% bound to serum proteins, predominantly to albumin and to a lesser extent to SHBG. Metabolism DSG is metabolised via hydroxylation and dehydrogenation to the active metabolite ENG. ENG is metabolised via sulphate and glucuronide conjugation. Elimination ENG is eliminated with a mean half-life of approximately 30 hours, with no difference between single and multiple dosing. Steady-state levels in plasma are reached after 4-5 days. The serum clearance after i.v. administration of ENG is approximately 10 l per hour. Excretion of ENG and its metabolites either as free steroid or as conjugates, is with urine and faeces (ratio 1.5:1). In lactating women, ENG is excreted in breast milk with a milk/serum ratio of 0.37-0.55. Based on these data and an estimated milk intake of 150 ml/kg/day, 0.01 - 0.05 micrograms etonogestrel may be ingested by the infant.

5.3 Preclinical safety data

Toxicological studies did not reveal any effects other than those, that can be explained from the hormonal properties of desogestrel.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core: Lactose monohydrate Maize starch Povidone PVP K-30 Stearic acid All-rac-alpha-tocopherol

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Silica, colloidal anydrous Film coating: Tabcoat TC-white-IHS Hydroxypropyl Methyl Cellulose Polyethylene Glycol Talc Titanium Dioxide

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

1 Year. 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container

PVC/PVDC aluminium blister packs containing 1x28 film-coated tablets. PVC/PVDC aluminium blister packs containing 3x28 film-coated tablets. PVC/PVDC aluminium blister packs containing 6x28 film-coated tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Strandhaven Ltd T/A Somex Pharma High Road Ilford Essex IG3 8BS UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 15764/0044

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 09/11/2011 10 DATE OF REVISION OF THE TEXT

09/11/2011

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Module 3

Product Information Leaflets

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Module 4

Labelling

Blister (front side of foil):

Blister (inner side of roll):

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Carton:

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Module 5

Scientific Discussion

Introduction RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Desorex 75 micrograms film-coated tablets used as a hormonal contraceptive for systemic use could be approved.

EXECUTIVE SUMMARY Problem statement This Decentralised application was submitted under Article 10.1 of Directive 2001/83/EC, as amended. The applicant claims that that the proposed product is a generic version of the product Cerazette 75 microgram film-coated tablet (PL 00065/0159), which was first licensed to Organon Laboratories Ltd in the UK on 9 November 1998. The reference product has, therefore, been authorised in the EEA for at least 10 years and the legal basis of this application is acceptable. With the UK as the Reference Member State in this Decentralised Procedure (DCP), Strandhaven Ltd T/A Somex Pharma is applying for a Marketing Authorisation for Desorex 75 micrograms film-coated tablets in Cyprus. About the product Desorex is a hormonal contraceptive for oral administration (one 75 microgram tablet every 24 hours). The first tablet should be taken on the first day of menstrual bleeding. Thereafter, one tablet each day is to be taken continuously. Desorex is a progestogen-only pill that contains the progestogen desogestrel. It inhibits ovulation and increases the viscosity of cervical mucus. The pharmacological classification of the medicine is hormonal contraceptives for systemic use (ATC code G03AC09). General comments on the submitted dossier The submitted documentation in relation to the proposed type of product is considered to be of sufficient quality and is consistent with the current EU regulatory requirements. Satisfactory overall summaries of the dossier regarding the quality, non-clinical and clinical parts have been submitted. General comments on compliance with GMP, GLP, GCP and agreed ethical principles

GMP The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent

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authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. GLP No new non-clinical studies were submitted in support of this application, and none are needed for an application of this type. Since a literature review has been presented for the non-clinical aspects, it cannot be verified whether the studies cited were in compliance with the GLP regulations; however, it is assumed that the studies conducted by the originator would have been conducted in compliance with the standards prevailing at the time. GCP Statements have been provided confirming that the submitted bioequivalence study was conducted in compliance with Good Clinical Practices (GCP), as referenced in the ICH guidelines (ICH E6), local regulatory requirements, and the principles enunciated in the Declaration of Helsinki. SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance General information rINN: Desogestrel Chemical names: 13-ethyl-11-methylidene-18,19-dinor-17α-pregn-4-en-20-yn-

17-ol (PhEur) (17α)-13-ethyl-11-methylene-18,19-dinorpregn-4-en-20-yn-17-

ol 13β-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-

17β-ol Other name: Org 2969 CAS number: 54024-22-5 Structural formula:

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Molecular formula: C22H30O Molecular weight: 310.48 General Properties: Desogestrel is a white or almost white, crystalline powder, practically insoluble in water, sparingly soluble in n-hexane and slightly soluble in anhydrous ethanol and in ethyl acetate. LogP (octanol/water) = 4.27. Desogestrel has six asymmetric carbon atoms and 64 possible stereoisomers. The configuration of five of these carbon atoms is determined by the starting material used in the synthesis and unaltered during it. The correct configuration on C-17 is established via stereoselective manufacturing. Manufacturing process Synthesis of the drug substance from the designated starting material has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant Certificates of Analysis. Control The active substance desogestrel is the subject of a Ph Eur monograph. An appropriate specification is provided for the drug substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Appropriate proof-of-structure data have been supplied for the drug substance. All potential known impurities have been identified and characterised. Satisfactory Certificates of Analysis for all working standards have been provided. Batch analysis data are provided and comply with the proposed specification. Container closure system Satisfactory specifications and Certificates of Analysis have been provided for all packaging used to store the drug substance. Confirmation has been provided that the primary packaging complies with current guidelines concerning materials in contact with foodstuffs. Stability Appropriate stability data have been generated, supporting a suitable retest period when the drug substance is stored in the packaging proposed. Drug product Description and composition The drug product is a white to off white, circular, biconvex, film-coated tablet. Each tablet contains 75 micrograms desogestrel and the excipients lactose monohydrate, maize starch, povidone PVP K-30, stearic acid, All-rac-alpha-tocopherol and silica, colloidal anhydrous. The tablets are coated in Tabcoat TC-white-HIS, which comprises hydroxypropyl methyl cellulose, polyethylene glycol, talc and titanium dioxide.

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All excipients comply with their respective Ph Eur monograph, with the exception of Tabcoat TC-white-HIS, which is controlled to an appropriate in-house specification. In the absence of a Ph Eur monograph for this excipient, this is acceptable. Furthermore, all ingredients of Tabcoat TC-white-HIS comply with their respective Ph Eur monograph. Satisfactory Certificates of Analysis have been provided for all excipients. Suitable declarations issued by suppliers of the excipients to confirm compliance with the requirements of the relevant guideline and Directives with regard to TSE are provided. The lactose monohydrate is produced from milk from animals fit for human consumption. Pharmaceutical development The objective of the development programme was to produce a formulation similar to the innovator product, Cerazette 75 microgram film-coated tablet, manufactured by Organon Laboratories Ltd. A satisfactory account of the pharmaceutical development has been provided. Manufacturing process A satisfactory batch formula has been provided, along with an appropriate account of the manufacturing process. The manufacturing process has been validated using production-scale batches and has shown satisfactory results. Finished product specification The finished product specification is acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Container-closure system The finished product is stored in PVC/PVDC aluminium blister packs containing 1x28, 3x28 or 6x28 film-coated tablets. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with foodstuffs. Stability of the product Stability studies were performed in accordance with current guidelines on the finished product in the packaging proposed for marketing. The data from these studies support a shelf-life of 1 year for this product. This medicinal product does not require any special storage conditions. Product literature The SmPC, PILs and labels are pharmaceutically acceptable. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains.

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Expert report The pharmaceutical expert report has been written by an appropriately qualified professional and is a suitable summary of the pharmaceutical dossier. Quality conclusion There are no objections to the approval of Desorex 75 micrograms film-coated tablets from a quality point of view. Non-clinical aspects

Non-clinical overview The pharmacological, pharmacokinetic and toxicological properties of desogestrel are well known. As desogestrel is a well known active substance, no further studies are required and the applicant has provided none. An overview based on the literature is thus appropriate. The non-clinical overview has been written by a toxicologist. The overview, (dated March 2009) refers to 28 publications up to the year 2009. In view of the fact that the pharmaco-toxicological properties of desogestrel are well known, the overview is acceptable. Environmental risk assessment An in-depth environmental risk assessment has been conducted by the applicant, which is considered to be acceptable. Product literature The product literature is acceptable from a non-clinical point of view. Non-clinical conclusion There are no objections to the approval of Desorex 75 micrograms film-coated tablets from a non-clinical point of view.

Clinical aspects Product indications The indication given in the SmPC is in line with the indication given in the SmPC for the reference product. Posology and method of administration The posology and method of administration given in the SmPC are in line with those given in the SmPC for the reference product. Bioequivalence study A single centre, randomised, single dose, laboratory blinded, two period, two sequence crossover bioequivalence study was carried out. Test product: Desorex 75 micrograms film-coated tablets x 2 tablets Reference product: Cerazette 75 microgram film-coated tablet x 2 tablets

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Population studied 24 female subjects between 18 and 55 years of age were enrolled in the study. Inclusion and exclusion criteria were presented and acceptable. 21 volunteers completed both study periods. Three subjects withdrew; two due to medical events and one subject was withdrawn due to a positive blood test. The study drug was administered with water after an overnight fast. 18 blood samples were collected during each period at pre-dose and at intervals up to 72 hours after administration of each product, with a washout period of 28 days between study drug administration. 46 adverse events were experienced in 18 subjects. 25 occurred after administration of the test product and 26 after administration of the reference product. Analytical, pharmacokinetic and statistical methods The concentration of desogestrel was determined in plasma. The analytical, pharmacokinetic and statistical methods were adequate. Bioequivalence results

*Two of the subjects were included in the pharmacokinetic and statistical analysis only for Cmax parameters **Units are pg/mL for Cmax and pg.h/mL for AUC0-72 Bioequivalence conclusion A standard 2-period, 2-sequence bioequivalence study was conducted under fasting conditions. The study design was adequate to address bioequivalence. The bioequivalence study submitted by the applicant was performed according to the respective NfG and GCP requirements. The 90% CI for the ratio of AUC and Cmax lie within the acceptance criteria of 80-125%. The test product, Desorex 75 micrograms film-coated tablets, and the reference product, Cerazette 75 microgram film-coated tablet, were shown to be bioequivalent under fasting conditions. Pharmacodynamics The pharmacodynamic characteristics of desogestrel have been well-studied in the past. There would be no particular concerns for a generic medicinal product. No new data have been submitted and none are required. Clinical efficacy and safety No new efficacy data are presented and none is required. A comprehensive review of the published literature has been provided by the applicant, citing the well established clinical pharmacology, efficacy and safety of desogestrel. Pharmacovigilance system

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The RMS considers that the pharmacovigilance system fulfils the requirements. The applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the collection and notification of any adverse reaction suspected of occurring in the Community or in a third country. Risk management plan No safety concerns requiring additional risk minimization activities have been identified. A detailed RMP is not considered necessary for this application. Expert report A clinical overall summary, written by an appropriately qualified physician, has been provided and is a satisfactory, summary of the clinical part of the dossier. Product literature All product literature (SmPC, PILs and labelling) is medically satisfactory. Clinical conclusion There are no objections to the approval of Desorex 75 micrograms film-coated tablets from a clinical point of view.

Overall conclusion and benefit-risk assessment Quality The important quality characteristics of Desorex 75 micrograms film-coated tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. Non-clinical No new non-clinical data were submitted and none are required for applications of these type. Efficacy The use of desogestrel as a hormonal contraceptive for systemic use is well established. Bioequivalence has been demonstrated between the Desorex 75 micrograms film-coated tablets and its reference product. New efficacy data is, therefore, not needed. Safety No new or unexpected safety concerns arise from this application. The SmPC and PILs are satisfactory and consistent with those of the reference product. Satisfactory labelling has also been submitted. Benefit-risk assessment The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with desogestrel is considered to have demonstrated the therapeutic value of the compound. The benefit/risk balance is, therefore, considered to be acceptable. A Marketing Authorisation should be granted.