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Menopur 600 IU & 1200 IU Powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

UKPAR

TABLE OF CONTENTS Lay summary P2 Scientific discussion P3 Steps taken for assessment P41 Steps taken after assessment P42 Summary of product characteristics P43 Product information leaflet P62 Labelling P67

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Menopur 600 IU & 1200 IU Powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted Ferring Pharmaceuticals Limited a Marketing Authorisation for the medicinal products Menopur 600 IU & 1200 IU powder and solvent for solution for injection (PL 03194/0106-0107) on 25th October 2010. These applications were submitted as two standard abridged line extension applications of Menopur 75 IU powder and solvent for solution for injection (PL 03194/0074) in accordance with Article 8(3), known active substance, of Directive 2001/83/EC. These medicines are subject to restricted medical prescription and are indicated for treatment of female and male infertility in the following groups of patients: - Anovulation, including polycystic ovarian disease (PCOD) in women: Menopur can be used to stimulate follicle development in amenorrhoeic patients. Clomiphene (or a similar ovulation inducing agent which influences steroid feed-back mechanisms) is the preferred treatment for women with a variety of menstrual cycle disturbances, including luteal phase insufficiency with anovulatory cycles and with normal prolactin, and also amenorrhoeic patients with evidence of endogenous oestrogen production but normal prolactin and normal gonadotrophin levels. Non-responders may then be selected for menotrophin therapy. - Women undergoing controlled ovarian hyperstimulation: Menopur can induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)). - Hypogonadotrophic hypogonadism in men: Menopur may be given in combination with human chorionic gonadotrophin (e.g. Choragon) for the stimulation of spermatogenesis. Patients with primary testicular failure are usually unresponsive. Menopur contains lyophilised powder of the highly purified active ingredient menotrophin (highly purified human menopausal gonatrophin, HP hMG). Menotrophin (HP hMG) stimulates ovarian follicular growth and development as well as gonadal steroid production in women who do not have primary ovarian failure. Treatment with Menopur is usually followed by administration of human chorionic gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, to induce final follicular maturation and ovulation. The dose and dosage regimen of Menopur is dependent on the indication. A critical review of the non-clinical and clinical data presented to the MHRA demonstrated that Menopur is effective for the treatment of female and male infertility in the specified groups of patients. No new safety risks were identified and the safety profile of Menopur was considered to be acceptable. It was therefore judged that the benefits of using this product outweigh the risks, hence the application has been granted.

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Menopur 600 IU & 1200 IU Powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction P4 Pharmaceutical assessment P5 Pre-clinical assessment P15 Clinical assessment P19 Overall conclusions and risk benefit assessment P40

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INTRODUCTION

Based on the review of data on safety and efficacy the UK granted a Marketing Authorisation to Ferring Pharmaceuticals Limited for the medicinal products Menopur 600 IU & 1200 IU powder and solvent for solution for injection (PL 03194/0106-0107) on 25th October 2010. These applications were submitted as two standard abridged line extension applications of Menopur 75 IU powder and solvent for solution for injection (PL 03194/0074) in accordance with Article 8(3), known active substance, of Directive 2001/83/EC. These medicines are subject to restricted medical prescription and are indicated for treatment of female and male infertility in the following groups of patients: - Anovulation, including polycystic ovarian disease (PCOD) in women: Menopur can be used to stimulate follicle development in amenorrhoeic patients. Clomiphene (or a similar ovulation inducing agent which influences steroid feed-back mechanisms) is the preferred treatment for women with a variety of menstrual cycle disturbances, including luteal phase insufficiency with anovulatory cycles and with normal prolactin, and also amenorrhoeic patients with evidence of endogenous oestrogen production but normal prolactin and normal gonadotrophin levels. Non-responders may then be selected for menotrophin therapy. - Women undergoing controlled ovarian hyperstimulation: Menopur can induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)). - Hypogonadotrophic hypogonadism in men: Menopur may be given in combination with human chorionic gonadotrophin (e.g. Choragon) for the stimulation of spermatogenesis. Patients with primary testicular failure are usually unresponsive. Menopur is presented as a white to off-white lyophilised cake powder and a clear colourless solvent for solution for injection administered via intramuscular or subcutaneous injection. Menopur (the powder) is available in a 2ml glass vial with rubber stopper closed with a flip of seal and (the solvent) a 1ml pre-filled syringe with rubber tip cap and plunger stopper without needle. Each pack contains one vial of powder, one pre-filled syringe with solvent for reconstitution, one needle for reconstitution, nine alcohol pads and nine disposable syringes for administration graduated in FSH/LH units with pre-fixed needles. The powder must be reconstituted with the diluent prior to use and each reconstituted vial should be for individual patient use only. Menopur 600 IU contains HP hMG corresponding to follicle stimulating hormone (FSH) activity 600 IU and luteinizing hormone (LH) activity 600 IU. Menopur 1200 IU contains HP hMG corresponding to FSH activity 1200 IU and LH activity 1200 IU. Human chorionic gonadotrophin (hCG), is also present in Menopur and contributes to the overall LH activity. Follicle stimulating hormone and LH exert their effects through activation of G-protein gonadotrophin receptors in the plasma membrane. Human chorionic gonadotrophin binds to the LH/hCG receptor with a slightly higher affinity than LH. The dose and dosage regimen is dependent on the indication. The original licence for Menopur 75 IU powder and solvent for solution for injection (PL 03194/0074) was granted on 19th November 1999 and these subsequent line extensions to add two new strengths (600 IU and 1200 IU) were granted on 25th October 2010.

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QUALITY ASSESSMENT  1 REQUESTS FOR INSPECTION ACTION PRIOR TO AUTHORISATION Not applicable. 2 INTRODUCTION Menopur 600 IU and 1200 IU Powder and solvent for solution for injection contains lyophilised powder of highly purified Menotrophin (HP hMG) and is reconstituted with the solvent provided prior to use. Menopur 600 IU contains HP hMG corresponding to follicle stimulating hormone activity (FSH) 600 IU and luteinizing hormone activity (LH) 600 IU. Menopur 1200 IU contains HP hMG corresponding to FSH activity 1200 IU and LH activity 1200 IU. Menopur is produced from the urine of post menopausal women. Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in Menopur and contributes to the overall luteinizing hormone (LH) activity. Menopur 600 IU and 1200 IU lyophilised powder contains HP hMG and excipients (lactose monohydrate, polysorbate 20, sodium phosphate dibasic heptahydrate and phosphoric acid). The provided solvent for reconstitution contains excipients (metacresol and water for injection). HP hMG belongs to the pharmacotherapeutic group of gonadotrophins (ATC code: G03G A02). HP hMG, which contains both FSH and LH activity, stimulates ovarian follicular growth and development as well as gonadal steroid production in women who do not have primary ovarian failure. Treatment with Menopur is usually followed by administration of hCG to induce final follicular maturation and ovulation. 2.1 LEGAL BASIS Submitted in accordance with Directive 2001/83/EC; Article 8(3): known active substance. This is a line extension: addition of a new strength. The applicant holds a market authorisation for Menopur 75 IU Powder and Solvent for Solution for Injection. This is a National UK license (PL 03194/0074). 2.2 USE Menopur is indicated for the treatment of female and male infertility in the following clinical situations: Anovulation, including polycystic ovarian disease (PCOD), in women who have been unresponsive to treatment with clomiphene citrate. Controlled ovarian hyperstimulation to induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)). Hypogonadotrophic hypogonadism in men. It is intended for subcutaneous or intramuscular injection. 2.3 SCIENTIFIC ADVICE N/A

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2.4 LEGAL STATUS POM. 3 DRUG SUBSTANCE 3.1 GENERAL INFORMATION 3.1.1 Nomenclature The following names are used to identify gonadotrophins obtained from the urine of post-menopausal women having FSH and LH activity: INN/BP: Menotrophin USP: Menotropins Other non-proprietary names: human Menopausal Gonadotrophin (hMG). 3.1.2 Structure LH, hCG and FSH belong to the same family of glycoprotein hormones. The molecules are heterodimers composed of an alpha and a beta subunit held together by ionic and hydrophobic forces. While the alpha-subunit is common for these three gonadotrophins, the beta-subunits are unique, giving them their different biological characteristics. The alpha-subunit contains 92 amino-acids (aa) and two N-linked glycosylation sites at aa 52 and 78. The beta-subunit of hCG contains 145 aa and two N-linked (Asn13 and Asn30) and 4 O-linked glycosylation sites localised on the 25- to 30- aa carbozy-terminal extension. The beta-subunit of FSH contains 111 aa and two N-linked glycosylation sites (Asn7 and Asn24), while LH contains 121 aa and a single N-linked glycosylation site at Asn30. The carbohydrate side chains on the subunits are highly heterogenous, thus multiple isoforms of each glycoprotein exist. 3.1.3 General properties HP-hMG is an almost white or slightly yellow powder containing not less than 2000 IU of FSH and LH bioactivity per mg substance, and is soluble in water. 3.2 MANUFACTURE 3.2.1 Manufacturers The applicant has provided full details of drug substance manufacturers and QC testing sites. The MAH has provided current Good Manufacturing Practice (GMP) certificates from the relevant competent supervising authorities for all manufacturing sites. 3.2.2 Manufacturing process Urine is collected from postmenopausal women in Argentina and purified to obtain the final drug substance (hMG-HP). The applicant has provided satisfactory information regarding the extraction/purification of hMG-HP including a flow chart. In general the manufacturing process is satisfactorily described, including information relating to the filtration materials and sanitation/regeneration procedures for each of the chromatography columns.

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3.2.3 Control of materials Starting materials (Urine) Urine is donated on a voluntary basis with no incentives. Each donor is interviewed and asked to fill in a general health questionnaire (translated version included in the dossier) relating to addiction (drug/alcohol); infection (i.e. hepatitis, HIV), age, medication received, travel to UK/Ireland. Approved donors can withdraw at any time. Testing of the collected urine is adequate and satisfactorily described. Process Materials The quality of materials used during manufacture is acceptable. 3.2.4 Control of Critical Steps and Intermediates In process controls (IPC) are in place, with defined acceptance limits, for FSH activity (potency), yield and moisture content (where drying takes place) for each fraction. Process related controls for each process step are provided and, in general, there are appropriate process controls in place. 3.2.5 Process Validation The applicant has provided the summary of a retrospective validation carried on the manufacture of drug substance (DS). The consistency of the manufacturing process has been adequately demonstrated for each process step. 3.2.6 Manufacturing Process Development The manufacturing process development has been adequately decribed. 3.3 CHARACTERISATION Refer to section 3.1.2 for an overall summary of the alpha/beta chain structure and glycosylation sites. The action of FSH is mediated by a distinct receptor, while LH and hCG exert their actions through the same receptor (McFarland, Sprengel et al. 1989). In addition, the beta-chain of these two glycoproteins have 82% protein sequence homology which makes it difficult to accurately measure the specific content of LH and hCG in menotrophin drug substances. The applicant has provided an adequate summary of the characterisation methods used and their results.

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Summary of different molecular forms of LH and hCG isolated from urine

Given the history of safe use of this product and that it is already licensed, the characterisation of the process and product related impurities of the product is deemed acceptable. It is agreed that the level of ethanol in the final product is well below established safety limits. 3.4 CONTROL OF DRUG SUBSTANCE 3.4.1 Specification The applicant has provided the drug substance testing strategy and release specifications, which are compliant with the British Pharmacopoeia (BP). 3.4.2 Analytical Assay Procedures A summary of the non-compendial assay methods used for release testing have been provided. 3.4.3 Validation of Analytical Assays All the non-compendial analytical assays have been satisfactorily validated and their respective validation reports were provided. 3.4.4 Batch Analysis Representative batch release certification for several batches has been provided. All batches comply with the proposed specifications and the data confirm the quality of drug substance manufactured at commercial scale.

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3.4.5 Justification of the Specification Most of the release assays are justified as they comply with British Pharmacopoeia (BP) requirements. The non-BP specifications are justified on the basis of their validation data. The justifications are considered acceptable. 3.5 REFERENCE STANDARDS OR MATERIALS Potency The in-house working reference standards for potency determination are adequately calibrated and a description of the calibration protocol is provided. The current certificate of analysis for the reference material was provided. The 5 year re-test date is acceptable. Physicochemical The current certificate of analysis has been provided for the current working standard and is acceptable. 3.6 CONTAINER CLOSURE SYSTEM Storage of the drug substance has been adequately described and compatibility of the drug substance with the container is assured on the basis of the stability data presented in section 7 of the dossier. Shipping studies to demonstrate controlled cold chain shipment have been provided and are satisfactory. 3.7 STABILITY Appropriate stability studies have been undertaken. Batches have been assessed for potency, purity, IEF, water content, pyrogenicity, and microbial content and all stability indicating acceptance criteria were met for all batches. A post approval commitment, to place one batch of bulk hMG-HP on long-term stability has been provided. 4 DRUG PRODUCT 4.1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT Menopur 600 IU and 1200 IU are sterile, lyophilised powers, intended for injection after reconstitution with the co-packaged solvent (WFI+preservative). The 600 IU presentation will be reconstituted with one pre-filled syringe (1.1 ml) of solvent; the 1200 IU presentation with two pre-filled syringes with solvent for reconstitution. Detailed compositions of the 600 IU and 1200 IU presentations have been provided. 4.2 PHARMACEUTICAL DEVELOPMENT Drug product composition is changed compared to that of the 75 IU FSH/LH formulation (PL 03194/0074) in that there is now less polysorbate 20, slightly more lactose monohydrate, sodium phosphate dibasic heptahydrate is a new excipient, and pH adjustment is performed with a different reagent. A satisfactory account of the pharmaceutical development has been provided.

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4.3 MANUFACTURE 4.3.1 Manufacturers Details of the manufacturers and their responsibilities have been provided. Current GMP certificates for all the manufacturers have been provided and are satisfactory. 4.3.2 Batch Formula The batch formula for the 600 IU and 1200 IU presentations has been provided and is acceptable. 4.3.3 Description of Manufacturing Process The manufacturing process description is minimalistic, but gives an adequate overview of the process. 4.3.4 Control of Critical Steps The in-process control tests are considered sufficient to ensure consistency of production. 4.3.5 Process Validation Partial process validation has been undertaken using several batches including batches at pilot and full scale. Compounding and filtration pH and appearance controls on several batches of compounded bulk solution are provided and are within specification. Filter validation has been provided and is adequate. Bioburden results before filtration and after first filtration have been provided and satisfactorily meet specifications. Filling Filling homogeneity was validated using full scale batches at the beginning and end of filling. Overall the results confirm homogeneity of fill and all vials met the required specification. Lyophilisation Lyophilisation has been validated and is satisfactory. It has been demonstrated that drying is even throughout the lyophiliser. Stoppering and inspection The protocol and report for integrity testing have been provided and confirm the suitability of the container/closure system in relation to microbial exclusion. Batch analysis All specifications were met. 4.4 CONTROL OF EXCIPIENTS The excipients are Ph. Eur. compliant where possible, or USP compliant if corresponding EU monographs do not exist.

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None of the excipients are of human origin. Lactose monohydrate is derived from bovine milk, and is not considered a TSE relevant material. 4.5 CONTROL OF DRUG PRODUCT 4.5.1 Specifications Drug product specifications for the 600 IU and 1200 IU presentations have been provided and are compliant with the BP. 4.5.2 Analytical Procedures Pharmacopoeial methods are not described, which is acceptable. 4.5.3 Validation of Analytical Procedures Validation data has been supplied which adequately demonstrates that non-compendial analytical procedures have been appropriately validated. 4.5.4 Batch Analysis Batch data has been provided for all batches prepared and used in the validation exercised so far. All acceptance criteria were met, indicating consistency of manufacture. 4.5.5 Characterisation of Impurities Product-related impurities are considered to be degradation products, these were characterised in the drug substance. The applicant has demonstrated that process-related impurities in the product are well controlled. 4.5.6 Justification of the specification The specifications are justified on the basis of BP requirements for menotrophins for injection. Non-compendial specifications are justified on manufacturing capability and assay validation data. This is acceptable. 4.6 REFERENCE STANDARDS OR MATERIALS The reference standards have been detailed and are satisfactory. 4.7 CONTAINER CLOSURE SYSTEM The 2ml glass vial is made of type I glass and is stated to be compliant with current edition of Ph.Eur. A diagram of the vial is provided. The rubber stopper is type I and is stated to be compliant with current version of Ph.Eur. A diagram of the rubber is provided. A flip-off seal is used to obtain closure between the vial and the stopper. 4.8 STABILITY All stability data is derived from pilot and full scale batches of the 600 IU and 1200 IU presentations. Powder The batches manufactured and used in process validation have been assessed for stability. The applicant has provided comprehensive data from pilot and full scale batches over appropriate time periods which are sufficient to support a shelf-life of three years at 2-8oC.

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Reconstituted product The applicant has provided sufficient data to give assurance that the reconstituted product is stable for 28 days when stored at not more than 25±2oC. Photostability The data provided confirms the product is not degraded by light. Post approval commitments The applicant commits to re-evaluate the pH specification for drug product after 15 batches have been produced. The applicant commits that the first production scale batch of 600 IU strength and the first 2 production scale batches of 1200 IU strength will be tested according to the post-approval stability protocol. Any out of specification results will be reported to the authority. The applicant commits to provide homogeneity of metacresol content in the solvent at the beginning, middle and end of filling within 6 months of licensure. 5 SOLVENT 5.1 DESCRIPTION AND COMPOSITION OF SOLVENT The composition of the solvent has been detailed and is satisfactory. It will be presented in a glass pre-filled syringe (PFS). 5.2 PHARMACEUTICAL DEVELOPMENT Antimicrobial excipient As the solvent will be used in a multi-dose formulation, antimicrobial efficacy in aqueous solutions was of importance during formulation development. Antimicrobial efficacy of the drug product was shown in tests according to the Ph.Eur. pH The pH limits established for the solvent are in accordance with the pH requirement for Menotrophin for injection (BP). 5.3 MANUFACTURE 5.3.1 Manufacturers Manufacturer details for solvent manufacturer, QC testing, batch release and secondary packaging have been provided and are adequate. 5.3.2 Batch Formula The batch formula for the solvent has been detailed and is satisfactory and sufficient to manufacture a large quantity of pre-filled syringes (PFS). 5.3.3 Description of Manufacturing Process The manufacturing process is a standard procedure for terminally sterilised parenteral solutions. A flow diagram of the manufacturing process has been provided and is satisfactory. The manufacturing description provided is considered adequate. 5.3.4 Control of Critical Steps In-process controls in place during the manufacture of solvent have been detailed. These are considered adequate to ensure solvent quality.

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5.3.5 Process Validation The applicant has validated the manufacture of solvent using several full scale batches. 5.4 CONTROL OF EXCIPIENTS The excipient quality standard used has been detailed and is satisfactory. All excipients meet Ph.Eur. current edition. 5.5 CONTROL OF SOLVENT 5.5.1 Specifications The release specifications for solvent have been detailed and are considered suitable to ensure the quality of the solvent at the time of release. 5.5.2 Analytical Procedures The only procedure that is not a compendial method is content of m-cresol. The method description is provided and this is acceptable. 5.5.3 Validation of Analytical Procedures Overall, validation of the analytical procedures is considered satisfactory. 5.5.4 Batch Analysis Batch release data from stability study batches has been provided and all release specifications were met. 5.5.5 Characterisation of Impurities Not applicable. 5.5.6 Justification of Specification For most of the release tests, the specification set is based on Ph. Eur. requirements and are acceptable. Antimicrobial specification is justified based on its known activity at the prescribed concentration and its stability during storage. 5.6 REFERENCE STANDARDS The Certificate of Analysis for the current reference standard is provided and is acceptable. 5.7 CONTAINER CLOSURE The solvent is filled into glass syringe barrels 1 ml, long (glass type I according to Ph.Eur.). The silicon oil used is Ph. Eur. compliant. The rubber tip cap of the syringe is type I according to Ph.Eur. The syringe is closed with a rubber plunger stopper made of halobutyl rubber (type I according to Ph.Eur.). Overall, sufficient information is provided in relation to the container closure. 5.8 STABILITY The stability data presented supports the proposed 36 months shelf life at 2-8oC.

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6 APPENDICES 6.1 FACILITIES AND EQUIPMENT No information has been provided in relation to the facilities and equipment. This is acceptable as the manufacturing facilities are the same as for Menopur 75 IU, as such this information has already been assessed, and GMP compliance is demonstrated by the provision of GMP certification. 6.2 ADVENTITIOUS AGENTS SAFETY EVALUATION 6.2.1 Virus Validation of Manufacturing Process Validation of the manufacturing process in relation to its virus inactivation capacity was originally carried out in 1994, and additional studies were carried out in 2007/8. The data presented confirms the validation of the identified virus removal/inactivation stages of manufacture is compliant with current EU requirements. 6.2.2 Microbial safety Overall the microbial safety of the starting material and the drug product is considered satisfactory. 6.3 NOVEL EXCIPIENTS N/A 7 REGIONAL INFORMATION 7.1 PROCESS VALIDATION SCHEME FOR THE DRUG PRODUCT 7.2 MEDICAL DEVICE ISSUES Each Menopur 600 IU carton contains 1 needle for reconstitution and 9 disposable syringes for administration graduated in FSH/LH units with pre-fixed needles. The components have CE mark. Each Menopur 1200 IU carton contains 1 needle for reconstitution and 18 disposable syringes for administration graduated in FSH/LH units with pre-fixed needles. The components have CE mark. 7.3 TSE ISSUES EMEA/CHMP/BWP/472717/2009 reports on an expert workshop on CJD risk and urine derived products. They concluded that there is no epidemiological evidence of CJD or vCJD transmission by urine derived products, though this was not considered a sufficient basis to confirm the safety of such products. It was recommended that the manufacturers undertake an evaluation based on published data on the contribution of their manufacturing process to reduce/eliminate TSE agents. The applicant has provided a risk assessment of their product in relation to the potential for TSE agents to be present in the starting material, and the potential of their manufacturing process to reduce/eliminate those agents. The results demonstrate that there is a low risk of contaminated donations being introduced to the manufacturing process, and the process itself has at least one step that is effective in the removal of prions. This is considered acceptable. Assessor’s Overall Conclusions All quality issues have been addressed and this application can be approved.

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NON-CLINICAL ASSESSMENT 1 INTRODUCTION 1.1 Type of application and aspects on development These are National Applications for Menopur Powder and solvent for solution for injection 600 IU and 1200 IU submitted as line extensions to the already licensed Menopur 75 IU Powder & Solvent for Solution for Injection under Article 8(3). The proposed indications are: Treatment of female and male infertility in the following groups of patients: - Anovulation, including polycystic ovarian disease (PCOD) in women: Menopur can be used to stimulate follicle development in amenorrhoeic patients. Clomiphene (or a similar ovulation inducing agent which influences steroid feed-back mechanisms) is the preferred treatment for women with a variety of menstrual cycle disturbances, including luteal phase insufficiency with anovulatory cycles and with normal prolactin, and also amenorrhoeic patients with evidence of endogenous oestrogen production but normal prolactin and normal gonadotrophin levels. Non-responders may then be selected for menotrophin therapy. - Women undergoing controlled ovarian hyperstimulation: Menopur can induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)). - Hypogonadotrophic hypogonadism in men: Menopur may be given in combination with human chorionic gonadotrophin (e.g. Choragon) for the stimulation of spermatogenesis. Patients with primary testicular failure are usually unresponsive.

1.2 GLP aspects The two local tolerance toxicity studies have been conducted in accordance with GLP. 2 PHARMACOLOGY/PHARMACOKINETICS/TOXICOLOGY Menotrophin is a well-established active substance and there is a wealth of clinical data available following the use of the existing 75 IU preparation. The proposed drug substance is identical to that already licensed and as such no new pharmacology or pharmacokinetic studies have been submitted in support of this application and none are required. As with the existing product, Menopur 600 IU and 1200 IU will be administered clinically by either the subcutaneous or intramuscular route. However, minor changes have been made to the final formulation of the drug product, with the proposed products being reconstituted in two slightly different solvents than that used previously for Menopur 75 IU. More specifically, an aqueous solution of m-cresol (3 mg/mL) and sodium chloride (7 mg/mL) is replaced by an aqueous solution of m-cresol (3.3 mg/mL) only. The applicant has submitted two new non-clinical studies, described below, to investigate the local tolerance of Menopur in this new formulation.

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2.1 Local tolerance 28-day local tolerance study following administration of 600 IU Menopur in rabbits (Study 60093) Two groups of 4 (2 per sex) albino New Zealand White rabbits were treated with either 0.75 ml/450 IU Menopur Multidose (old formulation–aqueous solution of 3 mg/mL m-cresol and 7 mg/mL sodium chloride) by intramuscular injection or subcutaneous injection. Appropriate vehicle controls were used. The animals were dosed daily for 28 days. Clinical signs, reactions at the injection sites and body weights were observed during the study. At termination, the injected muscle was dissected and all changed muscle tissues were collected for determination of creatine kinase. The subcutaneous injection sites of animals were collected, fixed and examined histopathologically. A bluish coloration (bruising) was observed on some days at all injection sites, including the control sites. Minimal to slight swelling was observed at the subcutaneous injection sites, most often at the injection sites dosed with Menopur Multidose. These findings are normal for parenteral routes of administration. All animals gained weight during the study. However, some animals had periods of slight weight loss. Histopathology of the subcutaneous sites revealed a similar range of local tissue reactions for both formulations, although inflammation tended to be more pronounced at the Menopur Multidose sites. No statistically significant differences in depletion of creatine kinase were observed between the intramuscular injection sites treated with Menopur Multidose and the intramuscular injection sites treated with the vehicle. 28-day local tolerance study following administration of 1200 IU Menopur in rabbits (Study 67860) Two groups of 4 (2 per sex) albino New Zealand White rabbit were treated with either 0.75 mL/450 IU of Menopur 1200 IU (new formulation - aqueous solution of 3.3 mg/mL m-cresol) by intramuscular injection or subcutaneous injection. A saline solution was used as a control. The animals were dosed daily for 28 days. Clinical signs, reactions at the injection sites and body weights were observed during the study. At termination, the injected muscle was dissected and all changed muscle tissues were collected for determination of creatine kinase. The subcutaneous injection sites of animals were collected, fixed and examined histopathologically. Administration of Menopur was associated with decreased food intake and slight weight loss in some animals. However an overall weight gain was seen in all animals. In addition, a score 1 to 2 of erythema and oedema were observed only at the intramuscular injection sites treated with Menopur Multidose. A score 1 to 3 of erythema and a score 1 to 2 of oedema was observed at the subcutaneous injection sites, more frequently in those associated with Menopur Multidose. Histopathology of the subcutaneous sites revealed a similar range of local tissue reactions for Menopur Multidose and saline although inflammation tended to be more pronounced at the Menopur Multidose sites. No significant differences were observed in the creatine kinase depletion between the intramuscular injection sites treated with Menopur Multidose and the intramuscular injection sites treated with the saline, implying that no damage to the muscles occurred due to the test item. Assessor’s comment Local tolerance studies conducted by the applicant concluded that clinical administration of Menopur 600 IU and 1200 IU by the subcutaneous or intramuscular route in both solvents tested is unlikely to result in significant local irritation, other than the normal effects of parenteral administration. While no direct comparison between the already licensed product and the proposed products has been made experimentally, it is

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considered that no additional local toxicity is anticipated through use of the proposed product compared with that of the existing product. 2.2 Summary of Product Characteristics The non-clinical sections of the SPC are identical to those of the licensed product and are considered acceptable. 2.3 Environmental risk assessment An environmental risk assessment has been submitted by the applicant. The lack of a LogKow value is acceptable for this product. The PECsurface water has been calculated to be 0.001125 μg/L using a DOSEai of 0.225 mg.inh-1.d-1 and default values for Fpen, WASTEWinhab and DILUTION. While, 0.001 μg/L is considerably under the threshold triggering a Phase II assessment the fact that the proposed product is a potential endocrine disruptor has to be taken into consideration and the applicant has further refined the Fpen based on sales data and market share of Menopur 75 IU. Using the highest real penetration value obtained (Netherlands 2013, Fpen fraction value = 0.0000512), the revised PECsurface water is calculated to be 0.0000058 μg/L., which is approximately 1700 times below the action limit of 0.01 μg/L. Furthermore, the actual PECsurface water value is probably lower, as only approximately 9 % of administered Menopur 600 IU and 1200 IU appears to be excreted unchanged. Additional information The drug substance is considerably below the action limit warranting further studies; however it may still act as an endocrine disruptor at a level of 0.001 μg/L or the more accurate level of 0.0000058 μg/L. However, since the product consists of big proteins (approximately 50 kDa), it is not readily absorbed (which is why it is administered s.c. or i.m.). Furthermore, peptidases in the body or in the environment will break it down rapidly. Therefore it is highly unlikely that it will have an environmental effect. The drug is derived from naturally occurring hormones, but from the calculations below, it is clear that the additional environmental effects this might have are negligible: In an article by le Cotonnec et al., s.c. injection of 150 IU/day rFSH leads to a steady state plasma value of 8 IU/L. Hence, the elimination of rFSH was 105 IU/day (bioavailability is 70%). To compare these values with endogenously produced FSH in the population in the country where we assume the highest market penetration (the Netherlands), demographic statistics was used. Men and fertile women have a mean value of FSH in plasma of 5 IU/L, while postmenopausal women have an average of 60 IU/L. Children have less than 2.5 IU/L, which is negligible in further calculations. In the Dutch population, men and fertile women amount to 68% of the population and postmenopausal women 17%. The average plasma value of FSH for the population would therefore be = 0.68*5 + 0.17*60 = 3.4 + 10.2= 13.6 IU/L. If one assumes a similar clearance of endogenous FSH compared to the s.c. injection study, this would mean that endogenous FSH is produced in higher amounts than 105 IU/person/day (steady state plasma concentration is twice as high, 13.6 IU/person/day compared to 8 IU/person/day). The average contribution of Menopur 600 IU and 1200 IU to the total amount of FSH is maximally 0.023

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IU/day/person (using the sales estimates from 2013), which is only a fragment of the >105 IU/person/day endogenously produced and excreted FSH. The contribution of LH via the administration of Menopur 600 IU and 1200 IU is expected to be in the same range, since the endogenous levels of LH is comparable to those of FSH not further taking into account on a considerably shorter half-life of LH. Last but not least, the oral absorption of proteins of this size is practically nil. Therefore, the additional environmental effects of Menopur 600 IU and 1200 IU are clearly negligible. Taken together, the information provided in this assessment indicates that progression to phase II in the guideline is not warranted. Assessor’s comment The applicant has provided a satisfactory environmental risk assessment and acceptable argumentation to justify the lack of a need for a phase II assessment. The applicant has adequately justified the absence of a LogKow value in line with the guideline on environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00). 3 ASSESSOR’S OVERALL CONCLUSIONS Menotrophin is an established active substance and there is a wealth of clinical data available. As a line extension application, many non-clinical studies are not required and have not been provided. However, the applicant has conducted appropriate bridging studies which concluded that no additional local toxicity is expected following clinical use of the proposed product in the revised formulation. An acceptable environmental risk assessment has been conducted in line with the guideline on environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00) to allay persistence, bioaccumulation or toxicity concerns. The non-clinical sections of the SPC are identical to those of the licensed product and are acceptable. The granting of a Marketing Authorisation is recommended from a non-clinical perspective.

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CLINICAL ASSESSMENT

1 INTRODUCTION 1.1 TYPE OF APPLICATION AND REGULATORY BACKGROUND The existing product Menopur is licensed in the UK as Menopur 75 IU Powder & Solvent for Solution for Injection. This is National abridged application for line extension submitted under Article 8(3) (known active substance) for 600 IU and 1200 IU strengths. 1.2 CLINICAL BACKGROUND Exogenous gonadotrophins have been used to treat infertility for approximately 50 years, first for ovulation induction in anovulatory women and later also in association with assisted reproductive technologies (ART). Since the late 1970s until the mid 1980s, menotrophins have been the only commercial gonadotrophin preparations used for the treatment of infertile women. Menotrophin as described in the British Pharmacopoeia possesses both FSH and LH activities. Currently, commercial gonadotrophin preparations used in clinical practice for ovarian stimulation include menotrophin preparations (primarily menotrophin products containing 1:1 ratio of FSH:LH activity) and FSH only preparations (which contain none or negligible LH activity). The recombinant FSH and highly purified FSH as well as the highly purified menotrophin were introduced in the mid-late 1990s and contain fewer non-specific protein impurities. These products therefore facilitate the subcutaneous self-administration by the patient due to a reduced frequency of local reactions. Menopur is a highly purified protein preparation of human menotrophin (human menopausal gonadotrophin, hMG) obtained from the urine of postmenopausal women, comprising both FSH and LH activity. The LH activity is mainly contributed to by human chorionic gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine. FSH as well as LH exerts its effects through activation of G-protein gonadotrophin receptors in the plasma membrane. Human chorionic gonadotrophin binds to the LH/hCG receptor, and with a slighter higher affinity than LH. The development of Menopur was aimed to produce a well tolerated highly purified human urinary menotrophin preparation for controlled ovarian hyperstimulation (COH) to induce the development of multiple follicles for ART, and in in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles and ovulation induction in anovulatory women. The rationale of the development of two new formulations, 600 IU and 1200 IU, both with a concentration of 600 IU/mL, is to provide products that are more convenient to use, especially when doses higher than 75 IU are requested. The proposed new formulations contain several dosages in one vial and the injection volume is therefore smaller compared to the currently approved 75 IU formulation, thereby minimising the inevitable stress and discomfort of injection for the patient. 1.3 INDICATIONS Treatment of female and male infertility in the following groups of patients:

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- Anovulation, including polycystic ovarian disease (PCOD) in women: Menopur can be used to stimulate follicle development in amenorrhoeic patients. Clomiphene (or a similar ovulation inducing agent which influences steroid feed-back mechanisms) is the preferred treatment for women with a variety of menstrual cycle disturbances, including luteal phase insufficiency with anovulatory cycles and with normal prolactin, and also amenorrhoeic patients with evidence of endogenous oestrogen production but normal prolactin and normal gonadotrophin levels. Non-responders may then be selected for menotrophin therapy.

- Women undergoing controlled ovarian hyperstimulation: Menopur can induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)).

- Hypogonadotrophic hypogonadism in men: Menopur may be given in combination with human chorionic gonadotrophin (e.g. Choragon) for the stimulation of spermatogenesis. Patients with primary testicular failure are usually unresponsive.

1.4 DOSE AND DOSE REGIMEN Anovulatory infertility (including PCOD): Menotrophin is administered to induce follicular maturation and is followed by treatment with chorionic gonadotrophin to stimulate ovulation and corpus luteum formation. The dosage and schedule of treatment must be determined according to the needs of each patient. Response in monitored by studying the patient’s urinary oestrogen excretion or by ultrasound visualisation of follicles. Menotrophin may be given daily by either intramuscular or subcutaneous injection to provide a dose of 75 to 150 units of FSH and 75 to 150 units of LH, and gradually adjusted if necessary until an adequate response is achieved, followed after 1 or 2 days by chorionic gonadotrophin. In menstruating patients, treatment should be started within the first 7 days of the menstrual cycle. The treatment course should be abandoned if no response is seen in 3 weeks. This treatment cycle may be repeated at least twice more if necessary. Alternatively, three equal doses of menotrophin, each providing 225 to 375 units of FSH with 225 to 375 units of LH, may be given on alternate days followed by chorionic gonadotrophin one week after the first dose. In the daily therapy schedule, the dose is gradually increased until oestrogen levels start to rise. The effective dose is then maintained until adequate pre-ovulatory oestrogen levels are reached. If oestrogen levels rise too rapidly, the dose should be decreased. As a measure of follicle maturity the following values can be taken: - total urinary oestrogen: 75–150 micrograms (270–540 nmol)/24 hours - plasma 17 beta-oestradiol: 400–800 micrograms (1500–3000 pmol/L) When adequate pre-ovulatory oestrogen levels have been reached, administration of Menopur is stopped, and ovulation may then be induced by administering human chorionic gonadotrophin at a dose of 5000–10000 IU.

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Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted reproductive technologies (ART): In in-vitro fertilisation (IVF) procedures or other assisted reproductive techniques, menotrophin is used in conjunction with chorionic gonadotrophin and sometimes also clomiphene citrate or a gonadorelin agonist. Stimulation of follicular growth is produced by menotrophin in a dose providing 75 to 300 units of FSH with 75 to 300 units of LH daily. Treatment with menotrophin, either alone or in conjunction with clomiphene or a gonadorelin agonist, is continued until an adequate response is obtained and the final injection of menotrophin is followed 1 or 2 days later with up to 10000 units of chorionic gonadotrophin. Maturation of follicles is monitored by measurement of oestrogen levels, ultrasound and/or clinical evaluation of oestrogen activity. It is recommended there should be at least 3 follicles greater than 17 mm in diameter with 17 beta-oestradiol levels of at least 3500 pmol/L (920 picograms/ml). Egg maturation occurs by administration of human chorionic gonadotrophin in a dose of 5000–10000 IU, 30–40 hours after the last Menopur injection. Human chorionic gonadotrophin should not be administered if these criteria have not been met. Egg retrieval is carried out 32–36 hours after the human chorionic gonadotrophin injection. Male infertility: Spermatogenesis is stimulated with chorionic gonadotrophin (1000–2000 IU two to three times a week) and then menotrophin is given in a dose of 75 or 150 units of FSH with 75 to 150 units of LH two of three times weekly. Treatment should be continued for at least 3 or 4 months. 1.5 GCP ASPECTS Relevant documentation and the assurance on GCP compliance were provided by the applicant and considered to be acceptable. 1.6 ORPHAN MEDICINAL PRODUCTS N/A. 1.7 PAEDIATRIC DEVELOPMENT PROGRAMME The product represents prescription only medicine and does not fall under the scope of the legislation for requirement for paediatric investigational plan. 1.8 SCIENTIFIC ADVICE No national scientific advice was sought. 2 CLINICAL PHARMACOLOGY 2.1 PHARMACOKINETICS The applicant provided a literature based discussion on PK of FSH and LH. The absorption of large proteins, such as FSH and LH, can be described by two phases after a subcutaneous administration. The first phase is the diffusion of the drug through

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the extracellular matrix at the site of injection to the nearest lymph capillary wall. The second phase is the uptake of drug into the lymph capillaries and subsequent distribution, eventually into the blood stream. This contrasts to molecules smaller than 16–20 kDa that are predominantly transported by the blood capillaries. The total volume of fluid that is drained by the lymphatic system has been estimated to 2–4 L/day, a small volume compared to the 10–20 fold volume that is reabsorbed through the vascular capillaries. The comparatively small volume drained into the lymphatic system, and thus the rather slow initial transportation rate, at least partly explains the rather slow but similar absorption of FSH into the vascular circulation after subcutaneous and intramuscular injection. In the bioequivalence study CS05 the single dose pharmacokinetics of FSH was investigated in down-regulated healthy women administered 450 IU of two different Menopur formulations, EU 75 IU and “former” 1200 IU. The FSH and LH values were baseline corrected to get an as correct picture as possible for the PK profile of the concentrations resulting from the added Menopur. The two formulations showed vey similar PK characteristics, as evidenced by e.g. the 90% CI for the point estimates of AUC and Cmax of FSH being well within the bioequivalence limits 0.80–1.25. The baseline corrected terminal half-life of FSH was approx 45–48 hours, tmax occurred after approx 24 hours, and the Cmax was 12.5–13.0 mIU/mL. The somewhat different results compared to the PK data included in the SPC for 75 IU strength may be due to the bioequivalence study CS05 being a single dose study, while previous results are derived from a multiple-dose setting, which is the clinical setting, with sampling for PK analysis after 7 days of Menopur treatment. Since the driving force of diffusion is the concentration gradient, a difference in concentration by a factor >2.5, as between the former 1200 IU and the 75 IU formulations in CS05, would not result in bioequivalence if the diffusion was rate limiting. It can therefore be concluded that the rate limiting step in the vascular absorption of FSH is the lymphatic flow rate and transportation of FSH, and not the initial diffusion from the site of injection to the lymph capillaries. Consequently, it is most likely that the limited difference in excipient composition in the current 1200 IU multidose formulation compared to the marketed 75 IU formulation does not have any impact on the PK. The pharmacokinetic parameters of LH associated with urinary menotrophin preparations have not been possible to clearly document due to the short half-life of LH and the contribution of endogenous LH. Also in the study CS05 the LH time-concentration curve did not permit any PK calculations. However, since hCG contributes to a major part of the LH activity in Menopur, also the PK of β-hCG was analysed in this study. The half-life was estimated to approximately 25–27 hours and the tmax to approximately 17–20 hours, which was in line with the small changes seen in the LH concentration. It should be noted that the doses of Menopur to be used in clinical practice are based on the extensive clinical experience with menotrophin products. Therefore, the pharmacokinetics of Menopur per se is of little importance when deciding the dosing and schedule of the product. 2.1.1 Intra- and inter-individual variability Marked inter-individual variability has been associated with pharmacokinetic evaluation of FSH, and previously has not been found to be related to the type of FSH preparation administered. Based on the literature available, no major differences in the

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pharmacokinetic profile of FSH that could have clinical implications have been observed among gonadotrophin preparations. 2.1.2 Special pharmacokinetic considerations in target population The BE study was carried out in down-regulated healthy women. 2.1.3 Special populations No clinical data in special populations was provided. 2.1.4 Assessor’s overall conclusions on pharmacokinetics Provided references to the original studies for Menopur 75 IU strength and the literature-based discussion on PK parameters for FSH/LH containing product is acceptable. The individual dose requirements for this product will be very much dependent upon individual requirements and therapeutic response to FSH and LH. 2.2 BIOEQUIVALENCE One bioequivalence study has been conducted in the clinical development programme for the Menopur 600 IU and 1200 IU marketing application Menopur 1200 IU Clinical Development Programme

2.2.1 Administrative details Study title/number: FE 999906 CS05, An open labelled, randomised, crossover, single-centre study investigating bioequivalence between Menopur 75 IU and Menopur 1200 IU after subcutaneous administration of 450 IU to healthy female subjects. Company/CRO responsible for conduct of study PAREXEL International GmbH Clinical Pharmacology Research Unit Klinikum Westend, Haus 18 Spandauer Damm 130, 4050 Berlin, Germany Sponsor: Ferring Pharmaceuticals A/S International Centre Kay Fiskers Plads 11 2300 Copenhagen S, Denmark Date of study 13/07/2006–30/03/2007

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GCP certification This study has been performed in compliance with GCP. 2.2.2 Test & Reference Products

Reference product is marketed in the UK. 2.2.3 Study design Open-labelled, randomised, single-dose, two-treatment, two-period, two-sequence crossover, single centre study. The injection volume in the two treatment arms was not the same due to different constituent contents in the two formulations. In a blinded study this would have required a double-dummy design. Since the primary endpoint of the study was based on objective laboratory measurements (serum concentrations of FSH), the additional logistics involved in applying a double-dummy design were not considered appropriate. The sample size calculations for a bioequivalence study with CV of 33%, expected ratio of 1, level of significance 10% (i.e. 5% for each of the comparisons), power 90% and limits 80–125% resulted in a sample size of 50. The assumptions mimicked a previous crossover study run in the U.S.A. where bioequivalence was shown between the two 75 IU formulations of Menopur. Given these assumptions, a power of 80% was still obtainable with a drop-out rate of 20% (n=10). The chosen Menopur dose was the highest marketed strength administered as a single dose within the labelled dose range (ART programme for stimulation of the ovaries). The dose was chosen to ensure that the systemic exposure was sufficiently high to allow for reliable measurements of serum concentrations of FSH. The PK sampling schedule was selected based on the existing information on PK characteristics of FSH. The washout period between the administrations was chosen as 14 days based on the half-life of FSH in Menopur, which is about 50 hours. Five half-lives, which are generally accepted as a sufficient wash-out period, of FSH in Menopur equals 11 days at minimum, and for practical reasons, a washout period of 14 days was chosen. Two administrations of a 1-month depot formulation of Decapeptyl were given to assure down-regulation and minimise the interference of endogenous FSH, LH and β-hCG on the PK assessments.

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Primary Objective: To determine bioequivalence between Menopur 75 IU and Menopur 1200 IU, based on FSH serum concentrations, after the administration of 450 IU of either formulation to healthy female subjects pre-treated with a GnRH agonist. Secondary Objectives: • To compare the safety and tolerability after treatment with the two formulations • To compare the pharmacokinetics of FSH, LH and β-hCG after the administration of 450 IU of either formulation Inclusion Criteria Each subject had to meet the following inclusion criteria before entry into the study: signed written Informed Consent; female, 21–39 years of age (both inclusive), combined oral contraceptives were taken for at least three months prior to Day –28, willing to stop using oral contraceptives during the study, i.e. from Day–28 to Day 25, a normal transvaginal ultrasound scan, PAP smear test and result of gynaecological examination at Screening and Day –1, excluding in particular pregnancy and lactation, gynaecological bleeding of unknown reasons, ovary cysts, tumours of uterus and ovary or breast cancer (according to Amendment No. 2), responded to GnRH agonist treatment defined as serum oestradiol ≤50 pg/mL at Day –3 and Day –1, a body mass index (BMI) between 19 kg/m2 and 27 kg/m2 and body weight between 50 kg and 100 kg. Body mass index and body weight outside these ranges were acceptable, if judged by the Investigator to be not clinically significant, negative virology/serology for Human Immunodeficiency Virus HIV-1, HIV-2, Hepatitis B (surface antigen) and Hepatitis C antibody, healthy according to medical history, physical examination, ECG, blood pressure and heart rate, and laboratory profile of blood, including coagulation factors, and urine negative drug screen during screening and on Day –1, and negative urine alcohol test on Day –1, non-smoker or a light smoker (less than ten cigarettes, or equivalent, per day). Exclusion Criteria Presence or a history of clinically significant diseases of the renal, hepatic, gastrointestinal, cardiovascular, musculoskeletal systems or presence or history of clinically significant psychiatric, immunological, endocrine or metabolic diseases; any medical or surgical condition that might have interfered with the absorption, distribution, metabolism or excretion of the drug, as judged by the Investigator, a history of oophorectomy; a history of cancer within the last 10 years except for adequately managed basal cell carcinoma and squameous cell carcinoma of the skin, present or a history of severe allergy, e.g. asthma or anaphylactic reactions. Ongoing pregnancy or breastfeeding. Hypersensitivity towards any component of Menopur or Decapeptyl, had received prescribed medication (except combined oral contraceptives), over-the-counter (OTC) medication, or herbal medicines within 2 weeks or 5 half-lives of the drug, whichever was longer, prior to first dose of Decapeptyl. Intake of up to 4 g/d dosed according to labelling was allowed. Evidence of any enlarged ovary or ovarial cysts, of gynaecological bleedings of unknown reason, of uterus or ovary tumours or breast cancer (according to Amendment No. 2). Evidence of function disorders (treated or non-treated) of the thyroid, adrenal cortex, of hyperprolactinaemia or of tumours of the pituitary gland and the hypothalamus (according to Amendment No. 2). History of alcohol and drug abuse.

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Each subject participated in the study for 53 days excluding the screening visit. They passed 14 ambulatory visits and two in-house stays of four days each. After screening, the study started with a run-in period of 28 days, during which Decapeptyl was given to down-regulate endogenously released FSH and LH. The two treatment periods lasted for 14 days each with blood sampling during the first 144 hours subsequent to dosing according to a pre-defined time schedule, followed by a washout period of 8 days (i.e. total time between administrations was 14 days). A follow-up examination was performed between Day 23 and Day 27. If no safety concern existed in the opinion of the Investigator, the subjects were instructed to call monthly by phone until the return of menstruation. During the post-treatment phase, only unexpected SAEs related to any of the study medications were collected. Number of subjects A total of 112 subjects were screened, 66 of whom were enrolled into the run-in phase and received two Decapeptyl administrations. Fifty subjects were randomised into one of two possible treatment sequences, while 16 subjects were not randomised for various reasons, the most common (7 subjects) being insufficient downregulation of oestradiol. Twenty-five subjects each were sequentially dosed with 450 IU of Menopur 75 IU and Menopur 1200 IU or vice versa. All randomised subjects received the study medication as intended.

Dose(s) administered (test/reference) During the run-in period the subjects received an intra-muscular administration of Decapeptyl on Days –28 and –7. A pre-filled syringe with Decapeptyl was suspended in 1 mL, giving a concentration of 3.75 mg/mL of which 1 mL was given in the gluteal muscle. Prepared Decapeptyl was administered immediately. At Day 0 subjects were randomised to receive either: • A single dose (450 IU) of Menopur 75 IU at Day 0 and a single dose (450 IU) of Menopur 1200 IU at Day 14 or: • A single dose (450 IU) of Menopur 1200 IU at Day 0 and a single dose (450 IU) of Menopur 75 IU at Day 14

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For Menopur 75 IU two sets of three vials each were reconstituted in 1 mL, resulting in a concentration of 225 IU/mL. The dose 450 IU was administered as two subcutaneous injections of 1 mL each. For Menopur 1200 IU, one vial was reconstituted in 2.2 mL, resulting in a final concentration of 600 IU/mL. The dose 450 IU was administered as one subcutaneous injection of 0.75 ml. During the run-in and treatment period, no concomitant medication was allowed, except for treatment of AEs when necessary, and paracetamol up to 4 g/d dosed according to labelling. Any concomitant medication used during the study or within the valid time range before first administration of Decapeptyl was recorded together with the main reason for its prescription, the dose, and dosage regimen. Other Restrictions Intake of products containing poppy seed (e.g. poppy cake) had to be avoided for a period of at least 48 hours before screening and at least 48 hours before Day –1 (residential session) to avoid analytical interference with the drug screen for opiates. Subjects had to abstain from drinking alcoholic and caffeine-containing beverages for 72 hours before the screening visit and all subsequent visits to the clinic. Pre-defined bioequivalence acceptance criteria Bioequivalence between the two treatment formulations was claimed if the 90% confidence interval for the ratio of treatment means of AUC0-144 and Cmax was included in the equivalence interval from 0.80 to 1.25. Method of data analysis The PK parameters were calculated by Department of Experimental Medicine, Ferring Pharmaceuticals A/S. The PK parameters for FSH, LH and β-hCG in serum were calculated by non-compartmental analysis (NCA) methods. FSH is an endogenously released hormone and despite down-regulation with the GnRH agonist, the serum levels of FSH may not fall below the lower limit of quantification (LLOQ) of the assay. Calculation of AUC0-∞ was therefore not applicable and bioequivalence was calculated for Cmax and AUC0-144 only. The pharmacokinetic analysis of FSH was done both without baseline correction and after subtraction of the baseline endogenous level from the concentration in each serum sample. The baseline endogenous level was determined separately for each treatment period as the mean of the FSH concentrations –1, –0.5 and 0 hours pre-dose on Days 0 and 14, respectively. Serum concentration values below LLOQ, or below 0 when baseline corrected, were excluded from the NCA as well as from the descriptive statistics on concentrations. The number of observations was adjusted accordingly. Missing values (e.g. no blood sample taken or no plasma concentration value obtained during bioanalysis) were excluded from the NCA and from the descriptive statistics on concentrations. The number of missing values was listed for each treatment. No formal statistical analysis of ‘outliers’ was planned. The parameters AUC0-144 and Cmax are log-normally distributed rather than following a normal distribution (i.e., data cannot be negative), and were therefore log-transformed (according to FDA guidance) before analysis of variance (ANOVA). The ANOVA model

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included the fixed effects ‘period’, ‘sequence’ and ‘treatment formulation’, and the random effect ‘subjects nested within sequence’. Carry-over effects were not taken in account since the period between administrations was considered sufficient for wash-out. The primary analysis was made on baseline-corrected PK parameters. An explorative analysis on un-corrected PK parameters was done as described above, taking baseline FSH levels into consideration. This was done in an analysis of co-variance (ANCOVA) model with the fixed effects ‘period’, ‘sequence’ and ‘treatment formulation’, and the random effect ‘subjects nested within sequence’, and with FSH baseline value (mean value of three consecutive measurements at time point –1, –0.5 and 0 hours) as a covariate. Amendments to the protocol Three amendments (including 2 non-substantial) were issued during the clinical study: Amendment No. 2 (substantial), dated 31 May 2006: The inclusion and exclusion criteria were amended to be more specific regarding contraindications of Menopur, i.e. inclusion criterion no 5 was rephrased and exclusion criteria were added. Criteria for study termination were added, as well as an additional safety test during screening to exclude malfunction of the thyroid. This amendment was initiated following the recommendations of the Ethics Committee. There were no implications for the CRF/EDC system, however, the stopping criteria for the whole study was included into the subject information. Results Bioequivalence between Menopur 1200 IU and Menopur 75 IU was determined based on the PK parameters AUC and C derived from baseline-corrected serum FSH concentrations. The maximum mean FSH serum concentrations were observed at about 24 hours post-dose and reached geometric means of 11.8 and 12.6 mIU/mL (baseline corrected data), respectively. Bioequivalence by Intra-individual Comparison of Menopur,1200 versus Menopur75 with Baseline-Corrected Serum FSH

Both, the geometric means of AUC and C of baseline-corrected FSH were slightly higher after administration of Menopur 75 IU compared to Menopur 1200 IU. The inter-individual variability, expressed as coefficient of variation (CV%), was moderate for both Menopur formulations and ranging for both AUC0-144 and Cmax 63-64%. Current SPC suggests that Cmax, is achievable within 12 hours following subcutaneous administration and this is broadly in line with results of the BE study.

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Bioequivalence by Intra-individual Comparison of Menopur,1200 IU versus Menopur,75 IU Based on Uncorrected FSH Concentrations with Mean FSH Baseline as Covariate (ANCOVA) and without (ANOVA)

The results of the ANCOVA and of the ANOVA based on uncorrected FSH serum concentrations were almost identical, showing that baseline levels of FSH had no relevant impact on the demonstration of bioequivalence between the two Menopur formulations. Mean (± SD) Baseline-Corrected Serum FSH Concentrations

Before administration of both Menopur formulations the geometric mean FSH serum concentrations at baseline (1, 0.5 and 0 hours pre-dose) ranged between 4.22 and 4.42 mIU/mL. Maximum individual FSH baseline concentrations measured were 13.99 mIU/mL and 21.12 mIU/mL before administration of Menopur 1200 IU and Menopur, 75 IU, respectively. The substantial difference in terminal half-life and apparent clearance of serum FSH between baseline corrected and uncorrected calculations for both formulations is most likely due to the fact that FSH is an endogenous substance that is naturally released into the circulation. Consequently, the observed concentration decay after administration of Menopur is not mere elimination, rather the sum of endogenous FSH release into the

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circulation and the true elimination from circulation. Thus, the baseline corrected values are likely to reflect the actual elimination rate more closely than the uncorrected values. LH There were no relevant differences evident between the LH concentration–time profiles of Menopur 1200 IU and Menopur 75 IU, both showing slightly fluctuating LH serum levels over time. The geometric means ranged between 0.59 and 0.66 mIU/mL at baseline and between 0.48 and 0.65 mIU/mL after administration of both Menopur formulations. Maximum geometric mean LH serum concentrations of about 0.8 and 0.7 mIU/mL were observed at about 24 and 20 hours after administration of Menopur 1200 and Menopur 75 IU, respectively. A meaningful derivation of PK parameters was not possible. Mean (± SD) Serum LH Concentrations

The plasma concentration profiles of LH as well as β-hCG were very similar after administration of either of the two formulations, emphasising the equivalence of Menopur 1200 IU and Menopur 75 IU. There were no withdrawals from the study and only minor deviations were encountered. All assays were validated. 2.2.4 Assessor's Comment

The design of the bioequivalence study for the products such as Menopur is difficult due to the presence of endogenous hormones, inability to fully down-regulate endogenous FSH and LH production and requirements for base-line adjustments of the endogenous levels.

The bioequivalence should normally be determined on the basis of both components in the product (FSH and LH). However, the different composition of oligosaccharides affects bioactivity and speed of degradation. The biologic half-life of LH is 20 minutes, shorter than that of FSH. Therefore formal BE determination for LH is impossible.

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The dose from a higher strength (1200 IU) was chosen to ensure that the systemic exposure was sufficiently high to allow for reliable measurements of serum concentrations of FSH. The PK sampling schedule was selected based on the existing information on PK characteristics of FSH.

The BE for FSH was demonstrated for AUC0-144 and Cmax and this is considered to be acceptable. The Cmax determined in the study is broadly in line with the value quoted in currently approved SPC for Menopur 75 IU.

The conduct of the study, analytical methodology and the PK analysis were of adequate quality.

2.2.5 Assessor's Conclusion on Bioequivalence The bioequivalence of Menopur 75 IU and Menopur 1200 IU was demonstrated. Since both 600 IU and 1200 IU strengths are manufactured using the same manufacturing process and have similar qualitative composition, and the BE was established using higher strength, the BE between the current 600 IU and 1200 IU formulations, and the marketed 75 IU formulation can be claimed. 2.3 PHARMACODYNAMICS Follicle size and oestradiol levels are well established pharmacodynamic markers of gonadotrophin treatment. 2.3.1 Assessor’s Overall Conclusions on Pharmacodynamics There is no formal requirement to conduct PD studies for this type of product with well established hormonal mechanism of action. 3 CLINICAL EFFICACY No efficacy studies were conducted. 3.1 SUPPORTIVE STUDIES The efficacy of Menopur for multiple ovarian follicular development in patients undergoing ART was evaluated in 2002. A total of 727 women were exposed to trial products in the Phase III pivotal clinical study submitted to support the efficacy of Menopur (75 IU). Of these, 373 women were exposed to Menopur and 354 to the reference product (recombinant follitropin alfa, Gonal-F, Serono). For the PP-population with one IVF/ICSI cycle, the ongoing pregnancy rate was 24.7% in the Menopur group and 22.4% in the Gonal-F group, and 24.2% and 21.8% for the ITT-population, well within the -10% non-inferiority limit established. These results were confirmed in the so called MERIT study.

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3.2 CLINICAL STUDIES IN SPECIAL POPULATIONS None. 3.3 COMBINED DATA AND META-ANALYSES None. 4 CLINICAL SAFETY 4.1 INTRODUCTION Menopur is a potent gonadotropic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Patients undergoing stimulation of follicular growth, whether in the frame of a treatment for anovulatory infertility or ART procedures may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended Menopur dosage and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. Acute interpretation of the indices of follicle development and maturation requires a physician who is experienced in the interpretation of the relevant tests. Currently approved in the UK SPC for Menopur contains in 4.4 relevant warnings on ovarian hyperstimulation syndrome, multiple pregnancies, miscarriages and abortions, reproductive system neoplasm’s, congenital malformations, and thromboembolic events. 4.2 PATIENT EXPOSURE In total, 66 subjects were exposed to Decapeptyl of whom 50 subjects were exposed to Menopur during the course of the study. During the run-in phase the cumulative exposure to Decapeptyl was 7.5 mg per subject provided in two single doses of 3.75 mg each on two separate occasions. The cumulative exposure to Menopur was 900 IU per subject, i.e. two single doses of 450 IU on two separate occasions and each 14 days apart. The single doses were provided as formulations Menopur 1200 IU or Menopur 75 IU and per subject in one of two possible sequences. 4.3 DEATHS, SERIOUS ADVERSE EVENTS AND COMMON ADVERSE EVENTS Overall Summary of Treatment Emergent Adverse Events

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All reported AEs except 3 serious (all headaches and reported with Menopur 75 IU) were of mild intensity. Menopur 1200 IU A total of 30 subjects (60%) reported 61 TEAEs and 24 (39%) of those were assessed by the investigator to be related to Menopur. Adverse events observed more than once and considered to be Menopur-related were headache (n=9), hot flushes (n=3), abdominal pain (n=2), dysgeusia (n=2) and paraesthesia (n=2). Most of these AEs were of mild intensity but 4 AEs of headache were considered as moderate. The most frequent TEAEs that were classified as not being related to Menopur were headache (n=10), hot flushes (n=9), and myalgia (n=3). Menopur 75 IU A total of 30 subjects (60%) reported 61 TEAEs, 20 of which were assessed by the investigator to be related to Menopur. The only adverse event observed more than once and considered to be Menopur-related was headache (n=15), 13 of which were of mild or moderate intensity while 2 cases were severe in intensity. The most frequent TEAEs that were classified as not being related to Menopur were headache (n=15), hot flushes (n=8), and sleep disorders (n=3). All non-related TEAEs but one case of severe headache were considered of mild or moderate intensity. In general, no clear pattern by incidence and nature of AEs was evident for AEs with or without relationship to Menopur. 4.4 DISCONTINUATION DUE TO ADVERSE EVENTS None of the subjects was withdrawn due to an AE. 4.5 LABORATORY FINDINGS In summary, clinically relevant deviations of blood chemistry, haematology, urine chemistry parameters and vital signs, physical findings and ECG parameters related to treatment with Menopur, were not evident. 4.6 SAFETY IN SPECIAL POPULATIONS None. 4.7 DRUG-SPECIFIC SAFETY CONSIDERATIONS Not known. 4.8 POST MARKETING EXPERIENCE Menopur was first approved in Denmark on 18 November 1999. As of 31 December 2007 Menopur is approved in 74 countries worldwide. The cumulative exposure to Menopur from 18 November 1999 to 31 December 2007 is estimated to 863,084 treatment cycles, corresponding to 345,234 patients. As of 31 August 2008, Ferring Global Pharmacovigilance has registered 253 cases of adverse events following treatment with Menopur. A total of 156 cases have been assessed as related to Menopur from first launch in November 1999 to 31 August 2008. In addition to the listed events, 36 cases of ineffective treatment were reported.

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All adverse drug reactions reported post-marketing

Deaths One fatal case due to pulmonary embolism and one fatal case due to multiple organ failure were reported. The causality of the pulmonary embolism was stated as questionable. The multiple organ failure was associated with OHSS with very limited information provided.

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Ovarian Hyperstimulation Syndrome (OHSS) The most frequent serious adverse event reported was OHSS, accounting for 40 reported cases. Ovarian Hyperstimulation Syndrome is a well known complication of COH and can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities. Although rarely reported, it could be accompanied with serious thromboembolic events. Women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity (Body Mass Index > 30 kg/m2) or thrombophilia may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotrophins. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thromboembolic events. A total of four cases of OHSS associated with thromboembolic events have been reported following treatment with Menopur. The current labelling for gonadotrophins provides information on the risk of thromboembolic complications. Adherence to the recommended dosage regimen can minimise risk of OHSS and its severe forms. Anaphylactic reactions One case of anaphylactic reaction and one case of anaphylactic shock following treatment with Menopur have been reported. Taking into consideration the biochemical entities of menotrophins (peptides) and their theoretical ability to trigger hypersensitive reaction, including immediate type, anaphylactic reaction has been added to the labelling for Menopur to section 4.8 Undesirable effects. 4.9 ASSESSOR’S OVERALL CONCLUSIONS ON CLINICAL SAFETY Single dose administration of Menopur 1200 IU and Menopur 75 IU was safe and well tolerated as assessed by AEs, vital signs, eggs, clinical laboratory tests and physical examination. The general nature and incidence of TEAEs upon treatment with Menopur was comparable with the pattern of non-treatment AEs observed during the run-in phase of the study prior to treatment with the Menopur. There were no deaths, no non-fatal treatment-emergent SAEs or other significant TEAEs in this study. The SOC most frequently affected were nervous system with overall 55 TEAEs (45% of all TEAEs), the majority being headache, and vascular disorders with a total of 22 TEAEs (18% of all TEAEs), mostly hot flushes. There were no clinically significant findings for vital signs, ECG, clinical laboratory parameters or physical examination. Postmarketing history of the product was relatively extensive and is well covered by current SPC. 5 PRODUCT LITERATURE 5.1 SPC The entire SPC except the Posology section due to new proposed strength remains unchanged.

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5.2 PATIENT INFORMATION LEAFLET The PIL appeared of good quality and readability. The design, layout and the content are acceptable. The diagrams and pictograms utilised are self-explanatory and accompanied with appropriate text. All key safety messages are reflected and in line with currently approved SPC. A readability test has previously been conducted on the patient information leaflet (PIL) for Menopur. The PIL tested relates to the treatment of female and male infertility. The results of the test are documented in a final report and indicate that >80% of participants were able to trace and answer correctly all questions from the questionnaire. Due to similarities in design, layout and contents of the PIL, the applicant provided a bridging report and this concludes that the Menopur PIL complies with the MHRA requirements for the PIL. 5.3 PHARMACOVIGILANCE SYSTEM The RMP and DDPS are satisfactory. 5.4 RISK MANAGEMENT PLAN Menopur 75 IU has been marketed for a number of years. It is anticipated that Menopur 1200 IU and 600 IU will replace some of the usage of Menopur 75 IU. SAFETY SPECIFICATION Non-Clinical Safety No extensive non-clinical programme of studies has been performed. No animal studies have been performed to assess reproductive and developmental toxicity because a number of human studies have been performed to assess teratogenicity and fertility. Genotoxicity and carcinogenicity studies have not been performed because gonadotrophins are naturally occurring proteins. Assessor’s Comments: This is acceptable. Clinical Safety Limitations of the Human Safety Database A total of 50 patients have been exposed to Menopur 1200 IU during the clinical study program, with 878 patients exposed to Menopur 75 IU. Populations not studied in the Pre-Approval Phase Menopur is only intended for use in the childbearing female population and therefore studies in men, children or the elderly have not been conducted. The main relevant exclusion criteria for clinical trials included patients with any clinically significant systemic disease such as insulin dependent diabetes; endocrine or metabolic abnormalities; ovarian cysts; abnormal cervical smear; tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus; pregnancy, lactation or contraindication to pregnancy and hypersensitivity.

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Post-authorisation Usage It is estimated that approximately 421,000 patients have been exposed to Menopur 75 IU, from first launch until 03 August 2008. Identified and Potential Interactions No drug/drug interaction studies have been conducted with Menopur in humans. Although there is no controlled clinical experience, it is expected that the concomitant use of Menopur and clomiphene citrate may enhance the follicular response. Pharmacological Class Effects The risks associated with preparations in this pharmacological class are well defined. One of the major identified risks associated with use of gonadotrophins is OHSS. Proteins and to a lesser extent peptides have a potential to induce hypersensitivity, including generalised allergic reaction. Identified Risks Patient undergoing stimulation for follicular growth may develop OHSS, the most frequent iatrogenic complication of controlled ovarian hyperstimulation. The incidence of OHSS for ART has been estimated to be up to 20%, but varies between studies. A recently published literature data suggests that the incidence of OHSS in non-selected population during controlled ovarian hyperstimulation for ART is about 12%, with the incidence of severe cases being about 4%. Potential risks Menopur is a polypeptide compound, capable of causing allergic reactions. Serious allergic reactions, including anaphylactic reaction, have not been reported in clinical study program either with Menopur 75 IU, or with Menopur 1200 IU. During the post marketing period, total of two cases of anaphylactic reactions have been reported following administration of Menopur 75 IU. Summary of Ongoing Safety Concerns The main safety concerns with Menopur 1200 IU and 600 IU are the identified risk of OHSS and the potential risk of hypersensitivity reactions. Experience in patients with hepatic or renal impairment is listed as important missing information. Assessor’s Comments: The safety specification is generally satisfactory. It is noted that there in no experience in patients with hepatic and renal impairment, however, extensive clinical and post marketing experience with Menopur 75 IU does not indicate any identified or potential safety concern regarding its use in patients with impaired hepatic and renal function. PHARMACOVIGILANCE PLAN Routine Pharmacovigilance Practices Routine pharmacovigilance is planned for all risks. Assessor’s Comments: Given the extensive experience with Menopur 75 IU this is acceptable.

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EVALUATION OF THE NEED FOR ADDITIONAL RISK MINIMISATION The applicant does not consider that there is any need for additional risk minimisation activities given the extensive experience with Menopur 75 IU. The potential for medication errors is not considered clinically significant when Menopur 600 IU and 1200 IU are used in accordance with the proposed instructions for use. Assessor’s Comments: The educational and patient information materials that will be used to minimise the risk of medication errors are satisfactory. Summary of the EU RMP EU Risk Management Plan by Safety Concern

Assessor’s Comments: This is satisfactory. 6 OVERALL CONCLUSION 6.1 RISK BENEFIT Menopur is a well tolerated and effective product in proposed indications. Seen in a perspective of cumulative experience and total exposure to Menopur, the safety profile is in line with the information stated in the SPC. A benefit of the 600 IU and 1200 IU multidose formulations that marketing approval is applied for, is that a wider range of doses can be administered in a smaller volume compared to the already marketed 75 IU formulation, thereby minimising the inevitable stress and discomfort in relation to an injection. The main difference between the 600 IU and 1200 IU multidose formulations and the marketed 75 IU product is the ionic strength. This is unlikely to have implications on protein absorbance and only expected to have implications on the local tolerance at the injection site, but the hypothetical increase in the risk of injection site inflammation due to lower osmolarity is rebutted by the repeat administration tolerance test in rabbits.

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Bioequivalence between existing 75 IU strength and new proposed 600 IU and 1200 IU strengths was demonstrated and formulation differences between strengths of the product discussed adequately. In relation to viral transmission risks outlined in the Quality assessment, the postmarketing history of Menopur was not accompanied with any reports of viral infections/transmission. There were no viral infection adverse event reporting in the BE study conducted as a part of this submission. Current CHMP position is also very clear that clinical studies are no longer considered to be adequate for the monitoring of viral transmission risks. On the basis of the efficacy and safety evidence provided, the B/R ratio for Menopur 600 IU and 1200 IU powder and solvent for solution for injection is considered to be positive. 6.2 RECOMMENDED CONDITIONS FOR MARKETING AUTHORISATION There are no clinical issues precluding the marketing authorisation of this product.

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OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY The important quality characteristics of Menopur 600 IU and 1200 IU powder and solvent for solution for injection are well defined and controlled. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL The proposed drug substance is identical to that already licensed and as such no new pharmacology or pharmacokinetic studies have been submitted in support of this application and none are required. The non-clinical studies provided to investigate the tolerance of Menopur in the new formulation are satisfactory. EFFICACY AND SAFETY The benefit of the new multidose formulations is that a wider range of doses can be administered in a smaller volume compared to the already marketed 75 IU formulation, thereby minimising stress and discomfort in relation to an injection. No new efficacy studies were conducted which is acceptable. The safety profile of Menopur is well known and no new or unexpected safety concerns arose from these applications. The SmPC, PIL and labelling are acceptable. BENEFIT-RISK ASSESSMENT No new non-clinical or clinical safety concerns have been identified. Sufficient clinical experience with Menopur 600 IU and 1200 IU powder and solvent for solution for injection is considered to have demonstrated the therapeutic value of the new multidose formulation. The benefit-risk balance is, therefore, considered to be positive.

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Menopur 600 IU & 1200 IU powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the marketing authorisation application on 26th June 2009 2 Following standard checks the MHRA informed the applicant that its application was

considered valid on 1st July 2009 3 Following assessment of the submitted data, a request for supplementary information

was sent to the applicant on 21st September 2009 4 The applicant submitted its response to the supplementary information request in a

letter dated 10th June 2010 5 Following assessment of the submitted data, a further request for supplementary

information was sent to the applicant on 30th June 2010 6 The applicant submitted its response to the supplementary information request in a

letter dated 16th September 2010 7 The application was finalised on 25th October 2010

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Menopur 600 IU & 1200 IU powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted

Application type

Scope Outcome

43

Summary of Product Characteristics

Menopur 600 IU & 1200 IU powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

44

1 NAME OF THE MEDICINAL PRODUCT MENOPUR® 600 IU Powder and solvent for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient Each vial of lyophilised product contains highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to 600IU human follicle stimulating hormone (FSH) and 600IU human luteinising hormone (LH) activity. Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in MENOPUR and contributes to the overall luteinizing hormone activity. For excipients see section 6.1

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection Appearance of powder: white to off-white lyophilised cake Appearance of solvent: clear colourless solution

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Treatment of female and male infertility in the following groups of patients: - Anovulation, including polycystic ovarian disease (PCOD) in women: MENOPUR can be used to stimulate follicle development in amenorrhoeic patients. Clomiphene (or a similar ovulation inducing agent which influences steroid feed-back mechanisms) is the preferred treatment for women with a variety of menstrual cycle disturbances, including luteal phase insufficiency with anovulatory cycles and with normal prolactin, and also amenorrhoeic patients with evidence of endogenous oestrogen production but normal prolactin and normal gonadotrophin levels. Non-responders may then be selected for menotrophin therapy. - Women undergoing controlled ovarian hyperstimulation: MENOPUR can induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)). - Hypogonadotrophic hypogonadism in men: MENOPUR may be given in combination with human chorionic gonadotrophin (e.g. Choragon) for the stimulation of spermatogenesis. Patients with primary testicular failure are usually unresponsive.

4.2 Posology and method of administration

Anovulatory infertility (including PCOD): Menotrophin is administered to induce follicular maturation and is followed by treatment with chorionic gonadotrophin to stimulate ovulation and corpus luteum formation.

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The dosage and schedule of treatment must be determined according to the needs of each patient. Response in monitored by studying the patient’s urinary oestrogen excretion or by ultrasound visualisation of follicles. Menotrophin may be given daily by either intramuscular or subcutaneous injection to provide a dose of 70 to 150 units of FSH and 70 to 150 units of LH, and gradually adjusted if necessary until an adequate response is achieved, followed after 1 or 2 days by chorionic gonadotrophin. In menstruating patients, treatment should be started within the first 7 days of the menstrual cycle. The treatment course should be abandoned if no response is seen in 3 weeks. This treatment cycle may be repeated at least twice more if necessary. Alternatively, three equal doses of menotrophin, each providing 225 to 375 units of FSH with 225 to 375 units of LH, may be given on alternate days followed by chorionic gonadotrophin one week after the first dose. In the daily therapy schedule, the dose is gradually increased until oestrogen levels start to rise. The effective dose is then maintained until adequate pre-ovulatory oestrogen levels are reached. If oestrogen levels rise too rapidly, the dose should be decreased. As a measure of follicle maturity the following values can be taken:

- total urinary oestrogen: 75 - 150 micrograms (270 – 540nmol)/24 hours - plasma 17 beta-oestradiol: 400 - 800 micrograms (1500 – 3000pmol/L)

When adequate pre-ovulatory oestrogen levels have been reached, administration of MENOPUR is stopped, and ovulation may then be induced by administering human chorionic gonadotrophin at a dose of 5000 - 10000 IU. Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted reproductive technologies (ART): In in-vitro fertilisation (IVF) procedures or other assisted reproductive techniques, menotrophin is used in conjunction with chorionic gonadotrophin and sometimes also clomiphene citrate or a gonadorelin agonist. Stimulation of follicular growth is produced by menotrophin in a dose providing 75 to 300 units of FSH with 75 to 300 units of LH daily. Treatment with menotrophin, either alone or in conjunction with clomiphene or a gonadorelin agonist, is continued until an adequate response is obtained and the final injection of menotrophin is followed 1 or 2 days later with up to 10000 units of chorionic gonadotrophin. Maturation of follicles is monitored by measurement of oestrogen levels, ultrasound and/or clinical evaluation of oestrogen activity. It is recommended there should be at least 3 follicles greater than 17mm in diameter with 17 beta-oestradiol levels of at least 3500pmol/L (920picograms/ml). Egg maturation occurs by administration of human chorionic gonadotrophin in a dose of 5000-10000 IU, 30 - 40 hours after the last MENOPUR injection. Human chorionic gonadotrophin should not be administered if these criteria have not been met. Egg retrieval is carried out 32 - 36 hours after the human chorionic gonadotrophin injection. Male infertility: Spermatogenesis is stimulated with chorionic gonadotrophin (1000 – 2000 IU two to three times a week) and then menotrophin is given in a dose of 75 or 150 units of FSH with 75 to 150 units of LH two of three times weekly. Treatment should be continued for at least 3 or 4 months. Children: Not recommended for use in children. Elderly:

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Not recommended for use in the elderly. Method of Administration: For intramuscular or subcutaneous use The powder must be reconstituted immediately with the solvent provided prior to use (see section 6.6). The reconstituted solution is for multiple injections and can be used for up to 28 days. Vigorous shaking should be avoided. The solution should not be used if it contains particles or if it is not clear.

4.3 Contraindications

Men and Women MENOPUR is contraindicated in men and women with: - Tumours of the pituitary or hypothalamic glands - Hypersensitivity to the active substance or any of the excipients used in the formulation (see section 6.1) Men - Tumours in the testes Women - Ovarian, uterine or mammary carcinoma - Pregnancy and lactation - Gynaecological haemorrhage of unknown aetiology - Ovarian cysts or enlarged ovaries not due to polycystic ovarian disease. In the following situations treatment outcome is unlikely to be favourable, and therefore MENOPUR should not be administrated: - Primary ovarian failure - Malformation of sexual organs incompatible with pregnancy - Fibroid tumours of the uterus incompatible with pregnancy - Structural abnormalities in which a satisfactory outcome cannot be expected, for example, tubal occlusion (unless superovulation is to be induced for IVF), ovarian dysgenesis, absent uterus or premature menopause.

4.4 Special warnings and precautions for use

MENOPUR is a potent gonadotropic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. In the treatment of female infertility, ovarian activity should be checked (by ultrasound and plasma 17 beta-oestradiol measurement) prior to MENOPUR administration. During treatment, these tests and urinary oestrogen measurement should be carried out at regular intervals, until stimulation occurs. Close supervision is imperative during treatment. See “posology and administration” for optimum response levels of urinary oestrogen and plasma 17 beta-oestradiol. Values below these ranges may indicate inadequate follicular development. There is considerable inter-patient variability in response to menotrophin administration, with a poor response to menotrophin in some patients. The lowest effective dose in relation to the treatment objective should be used. The first injection of MENOPUR should be performed under direct medical supervision. Before starting treatment, the couple’s infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.

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Patients undergoing stimulation of follicular growth, whether in the frame of a treatment for anovulatory infertility or ART procedures may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended MENOPUR dosage and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. Acute interpretation of the indices of follicle development and maturation requires a physician who is experienced in the interpretation of the relevant tests. Ovarian Hyperstimulation Syndrome (OHSS) OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and rarely, in the pericardial cavities. The severe form OHSS may be life-threatening and is characterised by large ovarian cysts (prone to rupture), acute abdominal pain, ascites, very often hydrothorax and occasionally thromboembolic phenomena. Other symptoms that may be observed include: abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, haemoperitoneum, pleural effusions and acute pulmonary distress. If urinary oestrogen levels exceed 540nmol (150 micrograms)/24 hours, or if plasma 17 beta-oestradiol levels exceed 3000pmol/L (800 picograms/ml), or if there is any steep rise in values, there is an increased risk of hyperstimulation and MENOPUR treatment should be immediately discontinued and human chorionic gonadotrophin withheld. Ultrasound will reveal any excessive follicular development and unintentional hyperstimulation. In the event of hyperstimulation, the patient should refrain from sexual intercourse or to use barrier contraception methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after the hCG administration. If during ultrasound, several mature follicles are visualised, human chorionic gonadotrophin should not be given as there is a risk of multiple ovulation and the occurrence of hyperstimulation syndrome. Adherence to recommended MENOPUR dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see sections 4.2 and 4.8). Patients undergoing superovulation may be at an increased risk of developing hyperstimulation in view of the excessive oestrogen response and multiple follicular development. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing, the patient hospitalised and specific therapy for OHSS started. This syndrome occurs with higher incidence in patients with polycystic ovarian disease.

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Multiple pregnancy Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the age of the patient. The patient should be advised of the potential risk of multiple births before starting treatment. Pregnancy wastage The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ART procedures than in the normal population. Ectopic pregnancy Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatment. The prevalence of ectopic pregnancy after IVF has been reported to be 2 to 5%, as compared to 1 to 1.5% in the general population. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established if treatment with gonadotrophins increases the baseline risk of these tumours in infertile women. Congenital malformation The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. Thromboembolic events In women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity (Body Mass Index >30kg/m2) or thrombophilia may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotrophin may further increase the risk. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thromboembolic events.

4.5 Interaction with other medicinal products and other forms of interaction

No drug/drug interaction studies have been conducted with MENOPUR in humans. Although there is no controlled clinical experience, it is expected that the concomitant use of MENOPUR and clomiphene citrate may enhance the follicular response. When using GnRH agonist for pituitary desensitization, a higher dose of MENOPUR may be necessary to achieve adequate follicular response.

4.6 Pregnancy and lactation

MENOPUR should not be given during pregnancy or to lactating mothers

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4.7 Effects on ability to drive and use machines None known

4.8 Undesirable effects The most frequently reported adverse drug reactions during treatment with MENOPUR in clinical trials are ovarian hyperstimulation, abdominal pain, headache, enlarged abdomen, inflammation at the injection site, pain at the injection site and nausea, with an incidence rate between 2% and 7%. The table below displays the main adverse drug reactions in women treated with MENOPUR in clinical trials according to body system and frequency. Body System Frequency Adverse Drug Reaction Central/Peripheral nervous system disorders

Common (>1/100<1/10)

Headache

Gastro-intestinal disorders

Common (>1/100<1/10)

Abdominal pain, enlarged abdomen, nausea and vomiting

Female reproductive disorders

Common (>1/100<1/10)

Ovarian hyperstimulation, Pelvic pain

Application site disorders

Common (>1/100<1/10)

Inflammation at injection site, pain at injection site

Vascular (extracardiac) disorders

Uncommon (>1/1,000<1/100)

Deep vein thrombosis

In very rare cases, long term use of menotrophin can lead to the formation of antibodies making treatment ineffectual. Very rare cases of allergic reactions, localised or generalised, and delayed-type hypersensitivity have been reported after treatment with gonadotrophin containing products.

4.9 Overdose

The acute toxicity of menotrophin has been shown to be very low. However, too high a dosage for more than one day may lead to hyperstimulation, which is categorised as mild, moderate or severe. Symptoms of overdosage usually appear 3 - 6 days after treatment with human chorionic gonadotrophin. Mild hyperstimulation - Symptoms include some abdominal swelling and pain, ovaries enlarged to about 5cm diameter. Therapy - rest; careful observation and symptomatic relief. Ovarian enlargement declines rapidly. Moderate hyperstimulation - Symptoms include more pronounced abdominal distension and pain, nausea, vomiting, occasional diarrhoea, ovaries enlarged up to 12cm diameter. Therapy - bed rest; close observation especially in the case of conception occurring, to detect any progression to severe hyperstimulation. Pelvic examination of enlarged ovaries should be gentle in order to avoid rupture of the cysts. Symptoms subside spontaneously over 2 - 3 weeks. Severe hyperstimulation - This is a rare but serious complication - symptoms include pronounced abdominal distension and pain, ascites, pleural effusion, decreased blood volume, reduced urine output, electrolyte imbalance and sometimes shock, ovaries enlarge to in excess of 12cm diameter. Therapy - hospitalisation; treatment should be conservative and concentrate on restoring blood volume and preventing shock. Acute symptoms subside over several days

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and ovaries return to normal over 20 - 40 days if conception does not occur - symptoms may be prolonged if conception occurs.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotrophins ATC code: G03G A02 Menotrophin is a gonadotrophin extracted from the urine of postmenopausal women, having both luteinising hormone and follicle stimulating hormone activity. It is given by intramuscular or subcutaneous injection in the treatment of male and female infertility. Menotrophin (HMG) directly affects the ovaries and the testes. HMG has a gametropic and steroidogenic effect. In the ovaries, the FSH-component in HMG induces an increase in the number of growing follicles and stimulates their development. FSH increases the production of oestradiol in the granulosa cells by aromatising androgens that originate in the Theca cells under the influence of the LH-component. In the testes, FSH induces the transformation of premature to mature Sertoli cells. It mainly causes the maturation of the seminal canals and the development of the spermatozoa. However, a high concentration of androgens within the testes is necessary and can be attained by a prior treatment using hCG.

5.2 Pharmacokinetic properties

HMG is not effective when taken orally and is injected either intramuscularly or subcutaneously. The biological effectiveness of HMG is mainly due to its FSH content. The pharmacokinetics of HMG following intramuscular or subcutaneous administration show great individual variation. The maximum serum level of FSH is reached approximately 18 hours after intramuscular injection and 12 hours after subcutaneous injection. After that, the serum level decreases by a half-life of approximately 55 hours following intramuscular administration and 50 hours following subcutaneous administration. Excretion of HMG, following administration, is predominantly renal. The pharmacokinetics of MENOPUR in patients with renal or hepatic impairment has not been investigated.

5.3 Preclinical safety data

Toxic effects caused by HMG are unknown in humans. There is no evidence of teratogenic, mutagenic or carcinogenic activity of HMG. Antibodies against HMG can be built up in single cases following repeated cyclical administration of HMG, causing the treatment to be ineffectual.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Powder: Lactose monohydrate Polysorbate 20 Sodium phosphate dibasic heptahydrate Phosphoric acid (concentrated) for pH adjustment Solvent: Metacresol Water for injection

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6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life Powder: 3 years Solvent: 3 years After reconstitution, the solution may be stored for a maximum of 28 days at room temperature

6.4 Special precautions for storage

Prior to reconstitution, store in a refrigerator at 2ºC - 8ºC. Do not freeze. Keep in the original container in order to protect from light. After reconstitution, the solution may be stored for a maximum of 28 days at room temperature, not more than 25ºC. Do not freeze.

6.5 Nature and contents of container

MENOPUR is available in the following containers and pack sizes: Powder: 2ml glass (type I) vial with rubber (halobutyl type I) stopper closed with a flip off seal. Solvent: 1ml pre-filled syringe (type I glass) with rubber (type I) tip cap and plunger stopper (halobutyl rubber type I), without needle. Each pack contains 1 vial of powder, 1 pre-filled syringe with solvent for reconstitution, 1 needle for reconstitution, 9 alcohol pads and 9 disposable syringes for administration graduated in FSH/LH units with pre-fixed needles.

6.6 Special precautions for disposal

The powder must be reconstituted with the diluent prior to use. Attach the reconstitution needle to the pre-filled syringe. Inject the total contents of the solvent into the vial containing the powder. The powder should dissolve quickly to a clear solution. If not, roll the vial gently between the hands until the solution is clear. Vigorous shaking should be avoided. The reconstituted solution should not be administered if it contains particles or is not clear. The administration syringes are graduated in FSH/LH units from 37.5 – 600 IU and supplied with needles in the Menopur multidose carton. Draw up the exact prescribed dose of reconstituted solution from the vial using one of the disposable syringes provided for injection and administer the dose immediately. Discard the syringe after use. Each reconstituted vial should be for individual patient use only. Any unused product or waste material should be disposed in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Ferring Pharmaceuticals Limited The Courtyard Waterside Drive Langley Berkshire SL3 6EZ United Kingdom

52

8 MARKETING AUTHORISATION NUMBER(S) PL 03194/0106

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 25/10/2010 10 DATE OF REVISION OF THE TEXT 25/10/2010

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1 NAME OF THE MEDICINAL PRODUCT MENOPUR® 1200IU Powder and solvent for solution for injection 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Active ingredient

Each vial of lyophilised product contains highly purified menotrophin (human menopausal gonadotrophin, HMG) corresponding to 1200IU human follicle stimulating hormone (FSH) and 1200IU human luteinising hormone (LH) activity. Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in MENOPUR and contributes to the overall luteinizing hormone activity. For excipients see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection Appearance of powder: white to off-white lyophilised cake Appearance of solvent: clear colourless solution

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Treatment of female and male infertility in the following groups of patients: − Anovulation, including polycystic ovarian disease (PCOD) in women:

MENOPUR can be used to stimulate follicle development in amenorrhoeic patients. Clomiphene (or a similar ovulation inducing agent which influences steroid feed-back mechanisms) is the preferred treatment for women with a variety of menstrual cycle disturbances, including luteal phase insufficiency with anovulatory cycles and with normal prolactin, and also amenorrhoeic patients with evidence of endogenous oestrogen production but normal prolactin and normal gonadotrophin levels. Non-responders may then be selected for menotrophin therapy.

− Women undergoing controlled ovarian hyperstimulation: MENOPUR can induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)).

− Hypogonadotrophic hypogonadism in men: MENOPUR may be given in combination with human chorionic gonadotrophin (e.g. Choragon) for the stimulation of spermatogenesis. Patients with primary testicular failure are usually unresponsive.

4.2 Posology and method of administration

Anovulatory infertility (including PCOD): Menotrophin is administered to induce follicular maturation and is followed by treatment with chorionic gonadotrophin to stimulate ovulation and corpus luteum formation.

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The dosage and schedule of treatment must be determined according to the needs of each patient. Response in monitored by studying the patient’s urinary oestrogen excretion or by ultrasound visualisation of follicles. Menotrophin may be given daily by either intramuscular or subcutaneous injection to provide a dose of 70 to 150 units of FSH and 70 to 150 units of LH, and gradually adjusted if necessary until an adequate response is achieved, followed after 1 or 2 days by chorionic gonadotrophin. In menstruating patients, treatment should be started within the first 7 days of the menstrual cycle. The treatment course should be abandoned if no response is seen in 3 weeks. This treatment cycle may be repeated at least twice more if necessary. Alternatively, three equal doses of menotrophin, each providing 225 to 375 units of FSH with 225 to 375 units of LH, may be given on alternate days followed by chorionic gonadotrophin one week after the first dose. In the daily therapy schedule, the dose is gradually increased until oestrogen levels start to rise. The effective dose is then maintained until adequate pre-ovulatory oestrogen levels are reached. If oestrogen levels rise too rapidly, the dose should be decreased. As a measure of follicle maturity the following values can be taken: − total urinary oestrogen: 75 - 150 micrograms (270 – 540nmol)/24 hours − plasma 17 beta-oestradiol: 400 - 800 micrograms (1500 – 3000pmol/L) When adequate pre-ovulatory oestrogen levels have been reached, administration of MENOPUR is stopped, and ovulation may then be induced by administering human chorionic gonadotrophin at a dose of 5000 - 10000 IU. Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted reproductive technologies (ART): In in-vitro fertilisation (IVF) procedures or other assisted reproductive techniques, menotrophin is used in conjunction with chorionic gonadotrophin and sometimes also clomiphene citrate or a gonadorelin agonist. Stimulation of follicular growth is produced by menotrophin in a dose providing 75 to 300 units of FSH with 75 to 300 units of LH daily. Treatment with menotrophin, either alone or in conjunction with clomiphene or a gonadorelin agonist, is continued until an adequate response is obtained and the final injection of menotrophin is followed 1 or 2 days later with up to 10000 units of chorionic gonadotrophin. Maturation of follicles is monitored by measurement of oestrogen levels, ultrasound and/or clinical evaluation of oestrogen activity. It is recommended there should be at least 3 follicles greater than 17mm in diameter with 17 beta-oestradiol levels of at least 3500pmol/L (920picograms/ml). Egg maturation occurs by administration of human chorionic gonadotrophin in a dose of 5000-10000 IU, 30 - 40 hours after the last MENOPUR injection. Human chorionic gonadotrophin should not be administered if these criteria have not been met. Egg retrieval is carried out 32 - 36 hours after the human chorionic gonadotrophin injection. Male infertility: Spermatogenesis is stimulated with chorionic gonadotrophin (1000 – 2000 IU two to three times a week) and then menotrophin is given in a dose of 75 or 150 units of FSH with 75 to 150 units of LH two of three times weekly. Treatment should be continued for at least 3 or 4 months. Children: Not recommended for use in children. Elderly:

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Not recommended for use in the elderly. Method of Administration: For intramuscular or subcutaneous use The powder must be reconstituted immediately with the solvent provided prior to use (see section 6.6). The reconstituted solution is for multiple injections and can be used for up to 28 days. Vigorous shaking should be avoided. The solution should not be used if it contains particles or if it is not clear.

4.3 Contraindications

Men and Women MENOPUR is contraindicated in men and women with: − Tumours of the pituitary or hypothalamic glands − Hypersensitivity to the active substance or any of the excipients used in the

formulation (see section 6.1) Men − Tumours in the testes Women − Ovarian, uterine or mammary carcinoma − Pregnancy and lactation − Gynaecological haemorrhage of unknown aetiology − Ovarian cysts or enlarged ovaries not due to polycystic ovarian disease. In the following situations treatment outcome is unlikely to be favourable, and therefore MENOPUR should not be administrated: − Primary ovarian failure − Malformation of sexual organs incompatible with pregnancy − Fibroid tumours of the uterus incompatible with pregnancy − Structural abnormalities in which a satisfactory outcome cannot be expected,

for example, tubal occlusion (unless superovulation is to be induced for IVF), ovarian dysgenesis, absent uterus or premature menopause.

4.4 Special warnings and precautions for use

MENOPUR is a potent gonadotropic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. In the treatment of female infertility, ovarian activity should be checked (by ultrasound and plasma 17 beta-oestradiol measurement) prior to MENOPUR administration. During treatment, these tests and urinary oestrogen measurement should be carried out at regular intervals, until stimulation occurs. Close supervision is imperative during treatment. See “posology and administration” for optimum response levels of urinary oestrogen and plasma 17 beta-oestradiol. Values below these ranges may indicate inadequate follicular development. There is considerable inter-patient variability in response to menotrophin administration, with a poor response to menotrophin in some patients. The lowest effective dose in relation to the treatment objective should be used. The first injection of MENOPUR should be performed under direct medical supervision. Before starting treatment, the couple’s infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.

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Patients undergoing stimulation of follicular growth, whether in the frame of a treatment for anovulatory infertility or ART procedures may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended MENOPUR dosage and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. Acute interpretation of the indices of follicle development and maturation requires a physician who is experienced in the interpretation of the relevant tests. Ovarian Hyperstimulation Syndrome (OHSS) OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and rarely, in the pericardial cavities. The severe form OHSS may be life-threatening and is characterised by large ovarian cysts (prone to rupture), acute abdominal pain, ascites, very often hydrothorax and occasionally thromboembolic phenomena. Other symptoms that may be observed include: abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, haemoperitoneum, pleural effusions and acute pulmonary distress. If urinary oestrogen levels exceed 540nmol (150 micrograms)/24 hours, or if plasma 17 beta-oestradiol levels exceed 3000pmol/L (800 picograms/ml), or if there is any steep rise in values, there is an increased risk of hyperstimulation and MENOPUR treatment should be immediately discontinued and human chorionic gonadotrophin withheld. Ultrasound will reveal any excessive follicular development and unintentional hyperstimulation. In the event of hyperstimulation, the patient should refrain from sexual intercourse or to use barrier contraception methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after the hCG administration. If during ultrasound, several mature follicles are visualised, human chorionic gonadotrophin should not be given as there is a risk of multiple ovulation and the occurrence of hyperstimulation syndrome. Adherence to recommended MENOPUR dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see sections 4.2 and 4.8). Patients undergoing superovulation may be at an increased risk of developing hyperstimulation in view of the excessive oestrogen response and multiple follicular development. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing, the patient hospitalised and specific therapy for OHSS started. This syndrome occurs with higher incidence in patients with polycystic ovarian disease.

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Multiple pregnancy Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the age of the patient. The patient should be advised of the potential risk of multiple births before starting treatment. Pregnancy wastage The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ART procedures than in the normal population. Ectopic pregnancy Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatment. The prevalence of ectopic pregnancy after IVF has been reported to be 2 to 5%, as compared to 1 to 1.5% in the general population. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established if treatment with gonadotrophins increases the baseline risk of these tumours in infertile women. Congenital malformation The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. Thromboembolic events In women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity (Body Mass Index >30kg/m2) or thrombophilia may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotrophin may further increase the risk. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thromboembolic events.

4.5 Interaction with other medicinal products and other forms of interaction

No drug/drug interaction studies have been conducted with MENOPUR in humans. Although there is no controlled clinical experience, it is expected that the concomitant use of MENOPUR and clomiphene citrate may enhance the follicular response. When using GnRH agonist for pituitary desensitization, a higher dose of MENOPUR may be necessary to achieve adequate follicular response.

4.6 Pregnancy and lactation

MENOPUR should not be given during pregnancy or to lactating mothers

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4.7 Effects on ability to drive and use machines None known

4.8 Undesirable effects

The most frequently reported adverse drug reactions during treatment with MENOPUR in clinical trials are ovarian hyperstimulation, abdominal pain, headache, enlarged abdomen, inflammation at the injection site, pain at the injection site and nausea, with an incidence rate between 2% and 7%. The table below displays the main adverse drug reactions in women treated with MENOPUR in clinical trials according to body system and frequency. Body System Frequency Adverse Drug Reaction Central/Peripheral nervous system disorders

Common (>1/100<1/10)

Headache

Gastro-intestinal disorders

Common (>1/100<1/10)

Abdominal pain, enlarged abdomen, nausea and vomiting

Female reproductive disorders

Common (>1/100<1/10)

Ovarian hyperstimulation, Pelvic pain

Application site disorders

Common (>1/100<1/10)

Inflammation at injection site, pain at injection site

Vascular (extracardiac) disorders

Uncommon (>1/1,000<1/100)

Deep vein thrombosis

In very rare cases, long term use of menotrophin can lead to the formation of antibodies making treatment ineffectual. Very rare cases of allergic reactions, localised or generalised, and delayed-type hypersensitivity have been reported after treatment with gonadotrophin containing products.

4.9 Overdose The acute toxicity of menotrophin has been shown to be very low. However, too high a dosage for more than one day may lead to hyperstimulation, which is categorised as mild, moderate or severe. Symptoms of overdosage usually appear 3 - 6 days after treatment with human chorionic gonadotrophin. Mild hyperstimulation - Symptoms include some abdominal swelling and pain, ovaries enlarged to about 5cm diameter. Therapy - rest; careful observation and symptomatic relief. Ovarian enlargement declines rapidly. Moderate hyperstimulation - Symptoms include more pronounced abdominal distension and pain, nausea, vomiting, occasional diarrhoea, ovaries enlarged up to 12cm diameter. Therapy - bed rest; close observation especially in the case of conception occurring, to detect any progression to severe hyperstimulation. Pelvic examination of enlarged ovaries should be gentle in order to avoid rupture of the cysts. Symptoms subside spontaneously over 2 - 3 weeks. Severe hyperstimulation - This is a rare but serious complication - symptoms include pronounced abdominal distension and pain, ascites, pleural effusion, decreased blood volume, reduced urine output, electrolyte imbalance and sometimes shock, ovaries enlarge to in excess of 12cm diameter. Therapy - hospitalisation; treatment should be conservative and concentrate on restoring blood volume and preventing shock. Acute symptoms subside over several days

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and ovaries return to normal over 20 - 40 days if conception does not occur - symptoms may be prolonged if conception occurs.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotrophins ATC code: G03G A02 Menotrophin is a gonadotrophin extracted from the urine of postmenopausal women, having both luteinising hormone and follicle stimulating hormone activity. It is given by intramuscular or subcutaneous injection in the treatment of male and female infertility. Menotrophin (HMG) directly affects the ovaries and the testes. HMG has a gametropic and steroidogenic effect. In the ovaries, the FSH-component in HMG induces an increase in the number of growing follicles and stimulates their development. FSH increases the production of oestradiol in the granulosa cells by aromatising androgens that originate in the Theca cells under the influence of the LH-component. In the testes, FSH induces the transformation of premature to mature Sertoli cells. It mainly causes the maturation of the seminal canals and the development of the spermatozoa. However, a high concentration of androgens within the testes is necessary and can be attained by a prior treatment using hCG.

5.2 Pharmacokinetic properties HMG is not effective when taken orally and is injected either intramuscularly or subcutaneously. The biological effectiveness of HMG is mainly due to its FSH content. The pharmacokinetics of HMG following intramuscular or subcutaneous administration show great individual variation. The maximum serum level of FSH is reached approximately 18 hours after intramuscular injection and 12 hours after subcutaneous injection. After that, the serum level decreases by a half-life of approximately 55 hours following intramuscular administration and 50 hours following subcutaneous administration. Excretion of HMG, following administration, is predominantly renal. The pharmacokinetics of MENOPUR in patients with renal or hepatic impairment has not been investigated.

5.3 Preclinical safety data

Toxic effects caused by HMG are unknown in humans. There is no evidence of teratogenic, mutagenic or carcinogenic activity of HMG. Antibodies against HMG can be built up in single cases following repeated cyclical administration of HMG, causing the treatment to be ineffectual.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Powder: Lactose monohydrate Polysorbate 20 Sodium phosphate dibasic heptahydrate Phosphoric acid (concentrated) for pH adjustment Solvent: Metacresol

Water for injection

60

6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Powder: 3 years Solvent: 3 years After reconstitution, the solution may be stored for a maximum of 28 days at room temperature.

6.4 Special precautions for storage

Prior to reconstitution, store in a refrigerator at 2ºC - 8ºC. Do not freeze. Keep in the original container in order to protect from light. After reconstitution, the solution may be stored for a maximum of 28 days at room temperature, not more than 25°C. Do not freeze.

6.5 Nature and contents of container

MENOPUR is available in the following containers and pack sizes: Powder: 2ml glass (type I) vial with rubber (halobutyl type I) stopper closed with a flip off seal. Solvent: 1ml pre-filled syringe (type I glass) with rubber (type I) tip cap and plunger stopper (halobutyl rubber type I), without needle. Each pack contains 1 vial of powder, 2 pre-filled syringes with solvent for reconstitution, 1 needle for reconstitution, 18 alcohol pads and 18 disposable syringes for administration graduated in FSH/LH units with pre-fixed needles.

6.6 Special precautions for disposal

The powder must be reconstituted with the diluent prior to use. Attach the reconstitution needle to the pre-filled syringe. Inject the total contents of the solvent into the vial containing the powder. The powder should dissolve quickly to a clear solution. If not, roll the vial gently between the hands until the solution is clear. Vigorous shaking should be avoided. The reconstituted solution should not be administered if it contains particles or is not clear. The administration syringes are graduated in FSH/LH units from 37.5 – 600 IU and supplied with needles in the Menopur multidose carton. Draw up the exact prescribed dose of reconstituted solution from the vial using one of the disposable syringes provided for injection and administer the dose immediately. Discard the syringe after use. Each reconstituted vial should be for individual patient use only. Any unused product or waste material should be disposed in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Ferring Pharmaceuticals Limited The Courtyard Waterside Drive Langley Berkshire SL3 6EZ United Kingdom

61

8 MARKETING AUTHORISATION NUMBER(S) PL 03194/0107 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 25/10/2010 10 DATE OF REVISION OF THE TEXT 25/10/2010

62

Patient Information Leaflet

Menopur 600 IU & 1200 IU powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

63

64

65

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Labelling

Menopur 600 IU & 1200 IU powder and solvent for solution for injection

(menotrophin)

PL 03194/0106-0107

68