DRIVING INNOVATION IN FERTILITY

Transcription

1 HCP FACT SHEET DRIVING INNOVATION IN FERTILITY FOUNDATION OF ISTITUTO FARMACOLOGIO SERONO Professor Cesare Serono, a leader in fertility research, established the Istituto Farmacologico Serono (IFS) in Rome (Italy). BASIS FOR SERONO TREATMENTS Piero Donini, an IFS chemist, successfully extracted and purified the first gonadotropin preparation from the urine of post-menopausal women. This achievement was the basis for Pergonal, Serono's first human menopausal gonadotropin (hmg) hormone s REGISTRATION OF PERGONAL 25 SERONO The first human menopausal gonadotropin (hmg) preparation for clinical use Pergonal 25 Serono was registered in Italy on May 22.2 EARLY 1962 FIRST BABY BORN WITH PERGONAL NEW HORMONE STIMULATING OVULATION TO ACHIEVE CONCEPTION Hypothalamus As purification procedures improved, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) could FSH and LH hormones are be extracted and separated from produced here human menopausal gonadotropin Pituitary gland (hmg) for the first time. Using these new processes, Serono developed Metrodin, a urinary FSH indicated for the stimulation of follicular development and the induction of ovulation s LH FSH A healthy baby girl, the first baby conceived after induction of ovulation with Serono s human menopausal gonadotropin (hmg), Pergonal, was born in Israel.4 SUCCESSFUL PREGNANCIES WITH SERONO S HORMONES Serono registered Profasi, a human chorionic gonadotropin (hcg), and 20 pregnancies were achieved with Pergonal and Profasi Elizabeth Jordan Carr, the first US IVF baby, was born on December 28 in Norfolk (US) through stimulation with Pergonal.5 Her mother Judy had come to the Jones Institute in Norfolk from Massachusetts where IVF was illegal SERONO S CETROTIDE PREVENTS PREMATURE OVULATION DURING IVF TREATMENT Serono s Cetrotide (cetrorelix acetate) was granted European marketing authorization. It is indicated for the prevention of premature ovulation in patients undergoing controlled ovarian stimulation, followed by oocyte pick-up and assisted reproductive techniques.9 Serono scientists successfully expressed human follicle-stimulating hormone (FSH) in a Chinese Hamster Ovarian cell line.6 This became the technological basis for the recombinant gonadotropin products portfolio. DECEMBER BIRTH TO THE FIRST AMERICAN IVF BABY, WITH A SERONO PRODUCT SUCCESS FOR THE BASIS OF THE RECOMBINANT PORTFOLIO 1997 FIRST VAGINAL PROGESTERONE GEL Crinone (8% vaginal progesterone gel) became the first product of its type in the UK when itwas launched for IVF pre-embryo transfer.8 MERCK S INNOVATION IN TECHNOLOGIES MERCK S LEADERSHIP IN DRUG DEVELOPMENT 1 of SERONO IS FIRST WITH RECOMBINANT FSH, OFFERING HIGH PURITY AND CONSISTENCY In a world-first, Serono s GONAL-f (follitropin alfa for injection) was approved as the first recombinant follicle-stimulating hormone (r-fsh). Following clinical trials to develop the drug, the twins Cedric and Karine were born on October in Switzerland and became the first babies born after treatment with GONAL-f.7

2 2000 NEW GENERATION RECOMBINANT GONADOTROPIN HORMONES Luveris (lutropin alfa) was granted European marketing authorization for use in combination with recombinant human follicle-stimulating hormone (r-hfsh) for the stimulation of follicular development in adult women with severe follicle-stimulating hormone (FSH) and luteinizing hormone (LH) deficiency OVULATION TRIGGER OVIDREL /OVITRELLE IS LAUNCHED OVIDREL /OVITRELLE (choriogonadotropin alfa) used to trigger ovulation in women receiving fertility treatment was granted approval by the US Food and Drug Administration (FDA). 11 A year later, it received European market authorization INNOVATIVE DEVICE BRINGS MORE COMFORT TO PATIENTS Serono s GONAL-f (follitropin alfa for injection) filled-by-mass injection pen was granted European marketing authorization (pictured right). 12 A later version of the pen (pictured left) won the 2015 Red Dot Design Award AWARDING RESEARCHERS FOR ADVANCING THE FERTILITY FIELD Merck Serono initiated the Grant for Fertility Innovation (GFI), thus committing to go beyond drugs and value the importance of the IVF laboratory and technologies. Since then, millions of Euros have been provided for translational research projects supporting advancement of science and innovative technologies in the fertility field PERGOVERIS COMES TO MARKET Pergoveris (r-hfsh 150IU and r-hlh 75IU) was granted European marketing authorization. It is indicated for the stimulation of follicular developmentin adult women with severe folliclestimulating hormone (FSH) and luteinizing hormone (LH) deficiency MERCK SERONO IS FORMED The two family-owned companies Merck and Serono formed Merck Serono. As of 2015, Merck Serono is referred to as the biopharma business of Merck to strengthen the company s brand. A focus on fertility is established as part of a strategic decision to streamline efforts to help women and couples to fulfill their dream of having a baby, and there is a focus on addressing patient needs and improving fertility treatment outcomes SELF-ADMINISTRATING INJECTION PENS FOR MERCK SERONO S FERTILITY TREATMENT Merck Serono received European approval for three pre-filled, ready-to-use pen injectors for self-administration of GONAL-f (as pictured) and one for OVIDREL /OVITRELLE were approved in Europe. 16 Two years later, the FDA approved the GONAL-f pens for the US market. EEVA TEST DESIGNED TO IMPROVE IVF OUTCOMES As part of the company's strategy to go beyond drugs, Merck Serono announced a strategic partnership with Auxogyn on the Eeva (Early Embryo Viability Assessment) Test, with Merck Serono providing strategic, scientific and medical support. 17 The collaboration began in 2010 when Merck Serono invested in Auxogyn through its corporate venture capital fund. The Eeva Test is a predictive test which assesses embryo development potential by automatically identifying critical parameters for embryo development based on an innovative, proprietary software. FORMATION OF THE FERTILITY TECHNOLOGIES UNIT Merck Serono established the Fertility Technologies unit as part of its Fertility franchise's commitment to drive innovation for the better of patients. The company received the commercialization rights for the first Fertility Technologies product the Eeva Test in Europe and Canada GLOBAL FERTILITY ALLIANCE Merck Serono formed the Global Fertility Alliance with Genea and Illumina to identify and work on improvements of fertility-related laboratory processes. 20 INNOVATION BEYOND DRUGS Merck Serono signed a global collaboration agreement with Genea Biomedx, extending the company s product portfolio in fertility technologies with the aim to improve outcomes in fertility treatment. This currently includes three products - Gavi TM, Geri TM, Gems TM - and a broad agreement to jointly develop other innovative technology products and services. 19 MERCK S INNOVATION IN TECHNOLOGIES MERCK S LEADERSHIP IN DRUG DEVELOPMENT 2 of 10

3 GROUND-BREAKING TECHNOLOGIES Merck makes the three ground-breaking fertility technologies, Gavi, Geri and Gems available for clinical use in Europe. Gavi is the world s first automated vitrification instrument, Geri is a benchtop incubator fitted with a time-lapse camera to capture images of embryos as they develop, Gems is the latest generation of Genea s culture media allowing for high quality embryo cultivation. Merck also launched Gavi oocyte protocol, which allows the freezing of oocytes and embryos, and Geri medium, which supports undisturbed embryo growth. 21 The world s first baby is born on 21 April in Australia through fertility treatment using Geri. 22 IMPROVED PREFILLED PEN Merck launched an award winning improved GONAL-f prefilled pen for enhanced ease-of-use. Patients, nurses and doctors, through feedback, helped to innovate and improve the design of the product. To date, GONAL-f has already helped to bring an estimated 2.5 million babies into the world OPENING OF THE CENTRE OF EXCELLENCE FOR FERTILITY Merck and Genea open the first Centre of Excellence (CoE) for fertility to provide fertility professionals with a strong understanding of the concepts, processes and techniques that are undertaken in clinics. The centre aims to help optimize procedures to improve treatment outcomes for couples that want to conceive and to help address the unmet needs in assisted reproductive treatment (ART). 26 LAUNCHES IN JAPAN 2016 Established fertility drugs Crinone and OVIDREL / OVITRELLE are launched in Japan, bringing new treatment options to women and couples faced with infertility NEW PARTNERS FOR GLOBAL FERTILITY ALLIANCE Growing the Global Fertility Alliance with new partners ZEISS and Hamilton Thorne Ltd. At the 2016 European Society of Human Reproduction and Embryology (ESHRE) s annual meeting in Helsinki (Finland), the alliance presented an update on its activities and announced the new members EVOLVING TECHNOLOGIES Merck integrates the innovative Eeva Test with the Geri incubation platform, bringing together individualized incubation and outcome prediction. The evolving products meet the articulated needs of healthcare professionals; these first-in-class technologies will provide embryologists with in-depth information and control over the environment in which the embryo grows to support healthy embryo development and assessment. 27 PERGOVERIS PEN The European Commission granted European marketing authorization for Merck s new Pergoveris Pen. The ready-touse pre-filled pen is the third of Merck s pens. The combination of FSH and LH in a pre-filled pen is the first of its kind, supporting patients with a specific deficiency combination. 28 MERCK S INNOVATION IN TECHNOLOGIES MERCK S LEADERSHIP IN DRUG DEVELOPMENT 3 of 10

4 REFERENCES 1. Rosenberg, E. (ed) (2013) The Human Testis: Proceedings of the Workshop Conference Held at Positano, Italy, April 23 25, Vol. 10. New York: Springer Science & Business Media 2. Lunenfeld, B. Historical perspectives in gonadotrophin therapy. Hum. Reprod. Update (6): Ares Serono, (1996) A Tale of Two Hormones - The Story of FSH and LH (Geneva: Imprimeries Reunies SA) 4. Haaretz (2002). The Good Father. [online] 30 May 2002.Available at: Last access: June Cohen, J. et al. The early days of IVF outside the UK. Hum. Reprod. Update (5): Howles, C.M. Genetic engineering of human FSH (Gonal-F ). Hum. Reprod. Update (2): Ares Serono, Ares-Serono s Gonal-f is First Pharmaceutical Product to Receive Approval in Europe Through the New Centralized Application Procedure. [press release] 23 October Available at: S+GONAL-+IS+THE+FI RST+PHARMACEUTICAL+PRODUCT+TO+RECEIVE...-a Last access: June Merck (2015). Crinone 8% Progesterone Vaginal Gel [online]available at: crinone.html 9. European Medicines Agency. Cetrotide: EPAR Product Information (June 2016). [online] Available at: en_gb/document_library/epar_-_summary_for_the_public/ human/000233/wc pdf 10. European Medicines Agency. Luveris: EPAR - Product Information. (February 2015) [online] Available at: docs/en_gb/document_library/epar_-_summary_for_the_public/ human/000292/wc pdf 11. European Medicines Agency. Ovitrelle: EPAR - Product Information. (July 2014) Available at: document_library/epar_-_summary_for_the_public/human/000320/ WC pdf Last access: May Serono, Serono Annual Report 2004 [report] Available at: PDF/ sra2004.pdf 13. Red Dot Award, [website] Available at: online-exhibition/work/?lang=en&code= &y=2015&c=167&a=0 14. Merck Serono, Merck s Fertility Treatment Pergoveris Approved in European Union. [press release] 29 June Available at: html?newsid=f9761f73c c a379c&newstype=1 15. Grant for Fertility Innovation, (2015). What is GFI? [website] Available at: html 16. Merck Serono, Merck Received European Approval for Three Pre-Filled, Ready-To-Use Pen Injectors for Fertility Treatment [press release] 4 July Available at: extnewsdetail. html?newsid=8af9a719c4d16b8bc12578c3002cd782&newstype=1 17. Merck Serono, Merck Serono and Auxogyn Announce Collaboration on Eeva Test [press release] 18 October Available at: 9E E/$File/ _PressReleaseMS_Auxogyn_ CollaborationEeva.pdf 18. Merck Serono Merck Serono Announces Exclusive License Agreement with Auxogyn for Eeva Test [press release] 3 April Available at: de/n/0/53819f0df9b5a74ac1257caf00252e40/$file/auxogyneng.pdf 19. Merck Serono, Merck Serono as Pioneer in Assisted Reproductive Treatments Takes Leading Role in Fertility Technologies Signing a Global Collaboration Agreement with Genea Biomedx. [press release] 28 May Available at: de/n/0/605a3adcd7e1a3f9c1257e52006d7f0b/$file/geneaeng.pdf 20. Merck Serono, Merck, Illumina and Genea Form the Global Fertility Alliance for Excellence in Assisted Reproductive Treatment. [press release] 8 June Available at: /N/0/612AB4D301C4780DC1257E5D006B408D/$File FertilityTechnologiesAllianceEng.pdf 21. Merck (2016). Merck Makes Pioneering Technologies Gavi, Geri and Gems Available to Fertility Clinics. [press release] 11 April Available at: html?newsid=a7f1c862f c1257f91003c5a08&newstype=1 22. Merck (2016). We re happy to announce the birth of the 1st baby girl born through IVF using our embryo incubator Geri [online] Available at: Merck Merck Set to Launch New Version of Fertility Pens. [press release] 3 February Available at: EE522B31052D6766C1257F4C0038A469/$File/Pen_2.0_EN.pdf Last access: June Merck (2016). Merck Welcomes ZEISS and Hamilton Thorne as New Members of the Global Fertility Alliance. [press release] 30 June Available at: html?newsid=e a715c309c1257fe1004d2cdd&newstype=1 25. Pharmaceutical and Medical Devices Agency (2016). FY 2016 New Drugs (April September) Available at: files/ pdf 26. Merck (2017). Merck and Genea Open Centre of Excellence for Fertility. [press release] 20 January Available at: com/en/media/extnewsdetail tml?newsid=19e84abeab4ac6d1c12580ad0043a88c&newstype=1 27. Merck (2017). New Merck Technology Aims to Further Optimize Embryo Incubation and Assessment. [press release] 10 March Available at: tml?newsid=19bb6f8d c12580dd004159a3&newstype=1 28. Merck (2017). European Commission Grants Approval for Merck s New Pergoveris Pen for Fertility Treatment. [press release] 10 May Available at: A3C73306EFF1DF65C125810E F/$File/PergoverisPen_ ECApproval.pdf The information contained is not intended for distribution in the USA. Any medical information is not intended as a substitute for informed medical advice. Information on products and devices mentioned in this document may vary by country. Patients and healthcare professionals should be advised to check in with local medical resources and regulatory authorities for information appropriate to their country. The Eeva (Early Embryo Viability Assessment) Test is available through Merck in the UK, Spain, Canada, Ireland, Austria, France, Germany, Italy, Portugal and the Nordics (Denmark, Finland, Norway and Sweden). The Eeva Test was in-licensed in 2014 from Auxogyn Inc. Progyny, Inc., formed in March 2015, is the combined entity of Auxogyn, Inc. and FertilityAuthority, LCC. 4 of 10

5 PRESCRIBING INFORMATION Abbreviated product information based on the GONAL-f EU SPC dated May 2017 Please refer to the Summary of Product Characteristics for further information GONAL-f 300 IU/0.5 ml (22 micrograms/0.5 ml), 450 IU/0.75 ml (33 micrograms /0.75 ml), 900 IU/1.5 ml (66 micrograms/1.5 ml) solution for injection in a pre-filled pen. Qualitative composition: Pre-filled pens containing follitropin alfa, recombinant human follicle stimulating hormone (r-hfsh) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. (1) Anovulation (including polycystic ovarian syndrome, PCOS) in adult women who have been unresponsive to treatment with clomiphene citrate. (2) Stimulation of multifollicular development in adult women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer and zygote intra-fallopian transfer. (3) In association with a luteinising hormone (LH) preparation for stimulation of follicular development in adult women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/L. (4) Stimulation of spermatogenesis in adult men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hcg) therapy. Dosage and administration: Initiate under the supervision of a physician experienced in the treatment of fertility disorders. For subcutaneous injection. Women with anovulation (including PCOS): Daily injections, starting by Day 7 of the cycle. Treatment should be tailored to the patient s response. Treatment typically commences at IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14-day intervals if required. Maximum daily dose is usually not higher than 225 IU FSH. If a patient fails to respond after 4 weeks of treatment, that cycle should be abandoned and treatment recommended at a higher starting dose. When an optimal response is obtained, a single injection of 250 micrograms r-hcg or 5,000 IU to 10,000 IU hcg should be administered hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of, and day following, hcg administration. Alternatively intrauterine insemination (IUI) may be performed. If the response is excessive, treatment should be stopped and the hcg withheld (see precautions). Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies: A commonly used regimen for superovulation involves the administration of IU of GONAL-f daily, commencing on day 2 or 3 of the cycle. Continue treatment until adequate follicular development has been achieved. Maximum daily dose is usually not higher than 450 IU daily. A single injection of 250 micrograms r-hcg or 5,000 IU up to 10,000 IU hcg is administered hours after the last GONAL-f injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone(gnrh) agonist or antagonist is commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. Women with anovulation resulting from severe LH and FSH deficiency: Treatment should be tailored according to response. Treatment may commence at 75 IU of lutropin alfa daily with 75 IU-150 IU FSH. If appropriate, the FSH dose should be adapted after 7-14 day intervals and by 37.5 IU-75 IU increments for up to 5 weeks. When an optimal response is obtained, a single injection of 250 micrograms rhcg or administer 5,000 IU to 10,000 IU hcg hours after the last lutropin alfa and GONAL-f injections.the patient is recommended to have coitus on the day of, and on the day following, hcg administration. Alternatively, IUI may be performed. If the response is excessive, treatment should be stopped and the hcg withheld. combination treatment may be continued. Current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Hypersensitivity to active substance or to any of the excipients, tumours of the hypothalamus or pituitary gland. In women, ovarian enlargement or cyst not due to polycystic ovarian syndrome, gynaecological haemorrhages of unknown aetiology, ovarian, uterine or mammary carcinoma or when an effective response cannot be obtained such as primary ovarian failure, malformations of sexual organs or fibroid tumours of the uterus incompatible with pregnancy. In men, primary testicular insufficiency. Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of infertility problems. Self-administration should only be performed by patients adequately trained and with access to expert advice. The first injection should be performed under direct medical supervision. Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Assess couple s infertility and putative contraindications for pregnancy before starting treatment. Monitor for ovarian enlargement or hyperstimulation. Excessive ovarian response to gonadotropin treatment can give rise to ovarian hyperstimulation syndrome (OHSS) with varying degrees of severity. Risk factors for OHSS include PCOS, as well as high or rapidly rising serum oestradiol levels. To minimise the risk of OHSS, adherence to recommended doses and administration schedule is important. Monitoring with ultrasound scans as well as oestradiol measurements are also recommended. There is evidence that hcg can trigger OHSS, and that the syndrome may be more severe and more protracted if pregnancy occurs. If OHSS occurs, withhold hcg and advise the patient to avoid coitus or use barrier methods of contraception for at least 4 days. Very rarely, severe OHSS may be complicated by ovarian torsion, pulmonary embolism, ischaemic stroke and myocardial infarction.patients should be advised of the potential risk of multiple births before starting treatment. Ectopic pregnancy is more common following ART and may occur in patients with prior tubal disease. Pregnancy loss is higher than in the normal population. Prevalence of congenital malformations may be slightly higher than after spontaneous conceptions. In women with recent or ongoing thromboembolic disease or those with generally recognised risk factors for thromboembolic events, treatment with gonadotropins increases the risk. There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. GONAL-f should not be used during breastfeeding. In men, semen analysis is recommended 4 6 months after the beginning of the treatment in assessing the response. GONAL-f should not be used in men when an effective response cannot be obtained. Interactions: Concomitant use of GONAL-f with other medicinal products used to stimulate ovulation (e.g. hcg, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of GONAL-f needed to elicit an adequate ovarian response. Undesirable effects Treatment in women: Very common: Headache, ovarian cysts, injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Common: abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea; mild or moderate OHSS (including associated symptomatology). Uncommon: Severe OHSS (including associated symptomatology). Rare: Complication of severe OHSS. Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock, thromboembolism (usually associated with severe OHSS), exacerbation or aggravation of asthma. Treatment in men: Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection), weight gain. Common: Acne, gynaecomastia, varicocele. Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock, exacerbation or aggravation of asthma. Men with hypogonadotrophic hypogonadism: 150 IU GONAL-f should be given three times a week, concomitantly with hcg, for a minimum of 4 months. If after this period the patient has not responded, the 5 of 10

6 Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/95/001/ Detailed information on this medicinal product is available on the website of the European Medicines Agency europa.eu. Date of preparation: January 2017 Abbreviated product information based Summary of Product Characteristics approved for the procedure DE/H/0146/002; dated February 2015; To be adapted to the locally approved Product Information Crinone 8% vaginal gel Progesterone Composition:1 g vaginal gel contains 80 mg of progesterone. Each applicator delivers g of vaginal gel containing 90 mg of progesterone. Progesterone supplementation of the luteal phase in adults as part of an ART (assisted reproductive technology) procedure. Dosage and Administration: From the day of embryo transfer, g Crinone vaginal gel (90 mg progesterone) should be inserted into the vagina once daily. Once the laboratory findings confirm pregnancy, this therapy should be continued for a total treatment duration of 30 days. Small white globules may appear as vaginal discharge possibly due to gel accumulation, up to several days after usage. Hypersensitivity to progesterone or any of the excipients, undiagnosed vaginal bleeding, porphyria, known or suspected malignancy of the breast or genital organs, thrombophlebitis, thromboembolic disorder, cerebral apoplexy, or patients with a history of these conditions, missed abortion. Crinone includes sorbic acid as an excipient. Sorbic acid may cause local skin reactions (e.g.contact dermatitis). Local skin reactions might also occur on the penis of the partner when having intercourse following vaginal application of Crinone. This may be prevented by the use of condoms. Gynaecological check-ups are required before and regularly under therapy with the drug; endometrial hyperplasia in particular should be ruled out as part of these controls under longer-term treatment. The pre-treatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear. If during therapy with Crinone, threatened abortion occurs, embryo viability should be established using rising HCG titers and/or ultrasound. In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding, non-functional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken. Because progestogens may cause some degree of fluid retention, conditions that might be influenced by this factor (e.g. epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation. The pathologist should be advised of progesterone therapy when relevant specimens are submitted. Careful use in the event of severe liver impairment. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. A decrease in glucose tolerance has been observed in a small number of patients on oestrogenprogestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy. The physician should be alert to the early manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorder, pulmonary embolism and retinal thrombosis). Should any of these thrombotic disorders occur or be suspected, the drug should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation. Interactions: The drug should not be administered simultaneously with other intravaginal therapies. No interaction studies have been performed. Side Effects: Common: somnolence, cramps, breast tenderness, headache. Uncommon to very rare: intermenstrual bleeding (spotting), vaginal irritation and other mild application site reactions. Frequency not known: hypersensitivity reactions e.g. generalized itchy skin rash. During post-marketing surveillance, clumping/coagulation/ accumulation of Crinone gel has been reported. These events are usually non-serious and appear with beige to brownish clumpy or sometimes cloudy white discharge. The gel clumping/coagulation/ accumulation can be associatedwith vaginal irritation, pain and swelling; very rarely, it might also cause cramps and vaginal bleeding. Marketing Authorisation Holder and Numbers in some countries: Merck Serono GmbH, Alsfelder Strasse 17, Darmstadt, Germany, MA number: Merck Sante, 37 Rue Saint Romain, Lyon, France; MA number , Merck, S.L., C/Maria de Molina, 40, Madrid, Spain; MA number Netherlands: Merck BV, Tupolevlaan 41-61, 1119 NW Schiphol-Rijk; Netherlands; MA number RVG Merck Sp. Z o.o, ul. Jutzenki 137, Warszawa, Poland; MA number For details for further countries please refer to the approved Summary of Product Characteristics in the country. Date of preparation: January 2017 Abbreviated product information based on the Cetrotide EU Summary of Product Characteristics (Last updated 28th June 2016) Cetrotide 0.25 mg powder and solvent for solution for injection Composition: Each vial contains 0.25 mg cetrorelix (as acetate). After reconstitution with the solvent provided, each ml of the solution contains 0.25 mg/ml cetrorelix. Prevention of premature ovulation in patients undergoing controlled ovarian stimulation followed by oocyte pick-up and assisted reproductive techniques. Dosage and administration: Cetrotide should only be prescribed by a specialist experienced in this field. The first administration of Cetrotide should be performed under the supervision of a physician and under conditions where treatment of possible allergic/pseudo-allergic reactions (including life-threatening anaphylaxis) is immediately available. The following injections may be self-administered as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the consequences of such a reaction and the need for immediate medical intervention. Cetrotide 0.25 mg is administered once daily, at 24 h intervals, either in the morning or in the evening. Administration in the morning: Treatment with Cetrotide should commence on day 5 or 6 of ovarian stimulation with gonadotropins and is continued throughout the gonadotrophin treatment period including the day of ovulation induction; Administration in the evening: Treatment with Cetrotide should commence on day 5 of ovarian stimulation with gonadotropins and continued throughout the gonadotrophin treatment period until the evening before the day of ovulation induction. Cetrotide is administered by subcutaneous injection into the lower abdominal wall. Hypersensitivity to the active substance or any structural analogue of GnRH, extrinsic peptide hormones or to any other excipients. During pregnancy and lactation, and in patients with severe renal impairment. Cases of allergic/pseudoallergic reactions, including life-threatening anaphylaxis with the first dose have been reported. Special care in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrotide is not advised in women with severe allergic conditions. During or following ovarian stimulation, ovarian hyperstimulation syndrome (OHSS) can occur. There is limited experience with Cetrotide during repeated ovarian stimulation procedures. Use in repeat cycles only after careful risk / benefit evaluation. The prevalence of congenital anomalies after the use of assisted reproductive technologies (ART) with or without GnRH antagonists may be slightly higher than after spontaneous conceptions although it is unclear whether this is related to factors inherent to the couple s infertility or to ART procedures. Limited data from clinical follow-up studies in 316 newborns of 6 of 10

7 women administered cetrorelix for infertility treatments suggested that cetrorelix does not increase the risk of congenital anomalies. Exercise caution in patients with hepatic impairment or mild to moderate renal impairment. Cetrorelix is contraindicated in patients with severe renal impairment. Interactions: No formal drug-drug interaction studies have been performed with cetrorelix. In vitro investigations have shown that interactions are unlikely with medicinal products that are metabolised by cytochrome P450 or glucuronised or conjugated in some other way. However, the possibility of interactions with gonadotropins or products that may induce histamine release in susceptible individuals cannot be totally excluded. Side effects: Common: Local injection site reactions e.g. erythema, pruritus and swelling. Mild to moderate OHSS (WHO grade I or II) can occur, which is an intrinsic risk of the stimulation procedure. Uncommon: Severe OHSS (WHO grade III). Systemic allergic/ pseudo-allergic reactions including life threatening anaphylaxis. Headache. Nausea. Prescribers should consult the summary of product characteristics in relation to other side-effects. Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/99/100/ Detailed information on this medicinal product is available on the website of the European Medicines Agency Item Code: GBPMLR/CET/0916/0006 Date of Preparation: September Note to affiliates: Abbreviated prescribing information should be reviewed and approved for local use as per local regulatory and code requirements. Reference to suspected adverse event reporting with national reporting system and Merck contact information ( and phone number) should be provided as per local regulations. Abbreviated product information based on the Luveris EU Summary of Product Characteristics dated February 2015 Please refer to the Summary of Product Characteristics for further information LUVERIS 75 IU powder and solvent for solution for injection lutropin alfa. Composition: One vial contains 75 IU of lutropin alfa (recombinant human luteinising hormone, r-hlh). Lutropin alfa is produced in genetically engineered Chinese Hamster Ovary (CHO) cells. Luveris in association with a Follicle Stimulating Hormone (FSH) preparation is recommended for the stimulation of follicular development in adult women with severe Luteinising Hormone (LH) and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level <1.2 IU/l. Dosage and administration: Treatment with Luveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems. The first injection of Luveris should be performed under direct medical supervision. Self-administration should only be performed by patients who are well-motivated, adequately trained and with access to expert advice. Safety, efficacy, and pharmacokinetics have not been established in patients with renal or hepatic impairment. Luveris should be administered concomitantly with follitropin alfa. Treatment should be tailored to the individual patient s response as assessed by measuring follicle size by ultrasound and oestrogen response. A recommended regimen commences at 75 IU of lutropin alfa (ie. one vial of Luveris) daily with IU FSH. Luveris is intended for subcutaneous administration. The powder should be reconstituted, immediately prior to use, with the solvent provided. Luveris has been shown to increase the ovarian sensitivity to follitropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5 IU-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.when an optimal response is obtained, a single injection of 250 micrograms of r-hcg or 5,000 IU to 10,000 IU hcg should be administered hours after the last Luveris and FSH injections. The patient is recommended to have coitus on the day of, and on the day following, hcg administration. Alternatively, intrauterine insemination (IUI) may be performed. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hcg withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. Do not use when a normal pregnancy is impossible (e.g. primary ovarian failure, malformation of the sexual organs incompatible with pregnancy or fibroid tumours of the uterus incompatible with pregnancy). Hypersensitivity to gonadotrophins or to any of the excipients; ovarian, uterine, or mammary carcinoma; tumours of the hypothalamus and pituitary gland; ovarian enlargement or cyst unrelated to polycystic ovarian disease and of unknown origin; gynaecological haemorrhages of unknown origin. Before starting treatment, the couple s infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. Patients should be evaluated for hypothyroidism, adrenocortical deficiency and hyperprolactinemia and appropriate specific treatment given. Porphyria In patients with porphyria or a family history of porphyria Luveris may increase the risk of an acute attack. Deterioration or a first appearance of this condition may require cessation of treatment. Ovarian Hyperstimulation Syndrome (OHSS) A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition 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.mild manifestations of OHSS may include abdominal pain, abdominal discomfort and distension, or enlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, ultrasound evidence of ascites or marked ovarian enlargement. Severe OHSS further includes symptoms such as severe ovarian enlargement, weight gain, dyspnoea or oliguria. Clinical evaluation may reveal signs such as hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, pleural effusions, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction. Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovarian syndrome, higher doses of exogenous gonadotropins, high absolute or rapidly rising serum estradiol levels and previous episodes of OHSS, large number of developing ovarian follicles and large number of oocytes retrieved in ART cycles. Adherence to recommended Luveris and FSH dosage and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well as estradiol measurements are recommended to early identify risk factors. There is evidence to suggest that hcg plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur, it is recommended that hcg be withheld and the patient be advised to refrain from coitus or use barrier contraceptive methods for at least 4 days. As OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event, patients should be followed for at least two weeks after hcg administration. Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing and that the patient be hospitalised and appropriate therapy be started. Ovarian torsion Ovarian torsion has been reported after treatment with other gonadotropins. This may be associated with other risk factors such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovarian syndrome. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion. Multiple pregnancy In patients undergoing induction of ovulation, the incidence of multiple pregnancy and births is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially high order, carry an increased risk of adverse maternal and perinatal outcomes.to minimise the risk of higher order multiple 7 of 10

8 pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing Assisted Reproductive Technology (ART) procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. Pregnancy loss The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than following natural conception. 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 treatments. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population. Congenital malformations The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This could be due to parental factors (e.g. maternal age, genetics), ART procedures and multiple pregnancies. Thromboembolic events In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, thrombophilia or severe obesity (body mass index >30 kg/m2), treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however, that pregnancy itself, as well as OHSS, also carries an increased risk of thromboembolic events. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. There is no indication for the use of Luveris during pregnancy. Luveris is not indicated during breast-feeding. Interactions: No interaction studies have been performed. Luveris should not be administered as a mixture with other medicinal products, in the same injection, except follitropin alfa for which studies have shown that co-administration does not significantly alter the activity, stability, pharmacokinetic nor pharmacodynamic properties of the active substances. Side effects: Summary of the safety profile Luveris is used for the stimulation of follicular development in association with follitropin alfa. In this context, it is difficult to attribute adverse reactions to any one of the substances used. In a clinical trial, mild and moderate injection site reactions (bruising, pain, redness, itching or swelling) were reported in 7.4 % and 0.9 % of the injections, respectively. No severe injection site reactions were reported. Ovarian Hyper-Stimulation Syndrome (OHSS) was observed in less than 6 % of patients treated with Luveris. No severe OHSS was reported (section 4.4). In rare instances, adnexal torsion (a complication of ovarian enlargement), and haemoperitoneum have been associated with human menopausal gonadotropin therapy. Although these adverse reactions were not observed, there is the possibility that they may also occur with Luveris. Ectopic pregnancy may also occur, especially in women with a history of prior tubal disease. List of adverse reactions: The following definitions apply to the frequency terminology used hereafter: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data). The following adverse reactions may be observed after administration of Luveris. Common: Injection site reaction (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection); Mild or moderate OHSS (including associated symptomatology), ovarian cyst, breast pain, pelvic pain; Abdominal pain, abdominal discomfort, nausea, vomiting, diarrhoea; Headache Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock; Thromboembolism, usually associated with severe OHSS. Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; United Kingdom; EU/1/00/155/ Detailed information on this medicinal product is available on the website of the European Medicines Agency Date of preparation: January 2017 Abbreviated product information based on the Ovitrelle EU Summary of Product Characteristics dated July 2014 Please refer to the Summary of Product Characteristics for further information OVITRELLE 250 micrograms/0.5 ml solution for injection in a pre-filled syringe OVITRELLE 250 micrograms solution for injection in a pre-filled pen choriogonadotropin alfa. Composition: One pre-filled syringe contains 250 micrograms choriogonadotropin alfa* (equivalent to approximately 6,500 IU) in 0.5 ml solution. One prefilled pen contains 250 microgramms choriogonadotropin alfa* (equivalent to approximately 6,500 IU). *recombinant human chorionic gonadotropin, r-hcg produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. (i) Adult women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF): Ovitrelle is administered to trigger final follicular maturation and luteinisation after stimulation of follicular growth. (ii) Anovulatory or oligo-ovulatory adult women: Ovitrelle is administered to trigger ovulation and luteinisation in anovulatory or oligo-ovulatory patients after stimulation of follicular growth. Dosage and administration: For subcutaneous administration. For single use only. Treatment with Ovitrelle should be performed under the supervision of a physician experienced in the treatment of fertility problems. The maximum dose is 250 micrograms. The following dose regimen should be used: (i) Women undergoing superovulation prior to assisted reproductive techniques: One pre-filled syringe or pen of Ovitrelle (250 micrograms) is administered 24 to 48 hours after the last administration of an FSH- or hmg preparation, i.e. when optimal stimulation of follicular growth is achieved. (ii) Anovulatory or oligo-ovulatory women: One pre-filled syringe or pen of Ovitrelle (250 micrograms) is administered 24 to 48 hours after optimal stimulation of follicular growth is achieved. The patient is recommended to have coitus on the day of, and the day after, Ovitrelle injection. Tumours of the hypothalamus and pituitary gland; Hypersensitivity to the active substance or to any of the excipients; Ovarian enlargement or cyst not due to polycystic ovarian disease; Gynaecological haemorrhages of unknown aetiology; Ovarian, uterine or mammary carcinoma; Extrauterine pregnancy in the previous 3 months; Active thromboembolic disorders; Primary ovarian failure; Malformations of sexual organs incompatible with pregnancy; Fibroid tumours of the uterus incompatible with pregnancy; Postmenopausal women. Self-administration of Ovitrelle should only be performed by patients who are adequately trained and have access to expert advice. Assess couple s infertility and putative contraindications for pregnancy before starting treatment. Evaluate for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia and pituitary or hypothalamic tumours, and appropriate specific treatment given. Safety, efficacy, and pharmacokinetics have not been established in patients with renal or hepatic impairment. There is no clinical experience with Ovitrelle in the treatment of other conditions (such as corpus luteum insufficiency or male conditions) therefore Ovitrelle is not indicated in these conditions. Ovarian Hyperstimulation Syndrome (OHSS) Patients undergoing ovarian stimulation are at an increased risk of developing OHSS due to multiple follicular development. Ovarian hyperstimulation syndrome may become a serious medical event characterised by large ovarian cysts, which are prone to rupture, weight gain, dyspnoea, oliguria or the presence of ascites within a clinical picture of circulatory dysfunction. Severe OHSS could be complicated in rare cases by haemoperitoneum, acute pulmonary distress, ovarian torsion, and thromboembolism. 8 of 10