GONAL-F THE COMPLEX PROCESS OF FERTILITY HORMONE DEFICIENCIES CAN LEAD TO INFERTILITY PROBLEMS WHAT IS GONAL-F? HCP FACT SHEET

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Leslie Arnold
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1 HCP FACT SHEET GONAL-F GONAL-f (recombinant follitropin alfa) is prescribed to supplement or replace naturally occurring folliclestimulating hormone (FSH), an essential hormone to treat infertility in both women and men. To date, 2.5 million babies 1 have been born worldwide with the support of GONAL-f. 9% of the global population of reproductive age is estimated to be infertile. Infertility affects one in six couples in the U.S. and in developing countries even one in four couples suffer from infertility. 2,3,4 Most cases of infertility can be treated through medically assisted reproduction, reproductive surgery, or drug treatment. 5 GONAL-f has been approved for use in the treatment of infertility in Europe since and since in the U.S., and is available in more than 100 countries worldwide*. The GONAL-f prefilled pen for self-administration was launched in and is currently available in 100 countries. Traditionally, gonadotropin hormones are extracted and purified from the urine of post-menopausal women. Merck was able to engineer its own genetic cell line with the ability to synthesize gonadotropin hormones through recombinant DNA technology. As a result, it became the first company in the world to synthesize r-hfsh. 9 *GONAL-f use for treatment of male infertility is approved in more than 80 countries worldwide. THE COMPLEX PROCESS OF FERTILITY Becoming pregnant is a complicated process and it s not uncommon for difficulties to arise. About one in ten couples need medical advice or help. Hormonal problems are the most common causes of anovulation, the failure of the ovary to release an egg. The process of ovulation depends upon a complex balance of hormones and their interactions to be successful. 3,10 HORMONE DEFICIENCIES CAN LEAD TO INFERTILITY PROBLEMS Hormones are key to fertility. The main hormones affecting fertility are produced by glands in the brain and the ovaries. A part of the brain called the hypothalamus produces GnRH (gonadotropin-releasing hormone). GnRH is a hormone that triggers the pituitary a pea-sized gland just below the hypothalamus to release two other hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH in turn start the process of ovulation (egg release) in the ovaries. During this process, the ovaries also produce estrogen and progesterone, both of which help prepare the uterus for pregnancy. WHAT IS GONAL-F? GONAL-f (follitropin alfa for injection) is a recombinant human follicle-stimulating hormone (r-hfsh) and is prescribed to supplement or replace naturally occurring FSH. The administration of GONAL-f is through subcutaneous injections. 6 1

GONAL-F IS AVAILABLE AS A PREFILLED PEN FOR PATIENT SELF- ADMINISTRATION Merck s injections devices are the first prefilled and multi-dose, ready-to-use pens for FSH treatment.

2 GONAL-F IS AVAILABLE AS A PREFILLED PEN FOR PATIENT SELF- ADMINISTRATION Merck s injections devices are the first prefilled and multi-dose, ready-to-use pens for FSH treatment. 11 The pens, including the GONAL-f pre-filled pen, are based on healthcare professionals and patients feedback to provide a common, prefilled and ready to use injection platform for Merck s gonadotropins. In 2016, Merck brought an updated version of the GONAL-f pen with various improved features to market, designed to bring an increased level of confidence to patients during their fertility treatment. 12 The delivery devices and the updated version of the GONAL-f pre-filled pen are not available in all markets. WHAT IS THE INDICATION FOR GONAL-F? For treatment in adult women: Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to treatment with clomiphene citrate. Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilization (IVF), gamete intra-fallopian transfer and zygote intrafallopian transfer. GONAL-f in association with a luteinizing hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/l. 6 For treatment in adult men: GONAL-f is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotropic hypogonadism with concomitant human Gonadotropin (hcg) therapy. 6 Sperm Sertoli cells Pituitary gland GONAL-f is perscribed to supplement or replace naturally occuring FSH FSH Embryo implantation In men FSH stimultes sertoli cells for sperm maturation and production FSH Uterus Ovary Egg In women FSH stimultes the egg to grow within a follicle 2

3 EFFICACY AND SAFETY PROFILE As the world s first r-hfsh, GONAL-f has a well-established clinical experience, with its safety profile based on 20 years of real-world pharmacovigilance data. 6 Clinical data demonstrates that treatment with GONAL-f (r-hfsh) results in significantly more embryos than with urinary-fsh (u-fsh). 13 GONAL-f is recognized for delivering continuous improvements: it is a recombinant gonadotropin available as a filled by mass third-generation pen injector device. This filled by mass feature improves dosing precision and performance in ovarian response. 14,15,16,17 Like all drugs, GONAL-f can cause side effects. Very common and common side effects include: 6 In women ovarian cysts headache abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhea ovarian hyperstimulation syndrome (OHSS) allergic reactions In men breast development, acne or weight gain gynaecomastia, varicocele injection site reactions Please refer to the Summary of Product Characteristics for the full list of adverse reactions. ABOUT INFERTILITY Infertility is a condition that is defined by the World Health Organization (WHO) as the failure to achieve pregnancy after 12 months or more of trying to conceive without using contraceptives. 18 For women over 35 years of age, a couple should see a doctor after trying to conceive for 6 months. 19 It is estimated that 9% of the global population of reproductive age are infertile and it affects one in six couples in the U.S. alone. 2,3 This number increases in developing countries to one in four couples who have been trying to have a baby for five years. 4 Since the early 1950s, demographic surveys have shown a steady reduction in birthrates in all European countries. In high-income countries, approximately 15% of the population is affected by infertility. This percentage is even higher in low-income countries (9-30%). 20 Infertility is not just attributed to women. Male conditions cause or contribute to approximately one-third of all infertility cases. 21,22 3

4 REFERENCES 1. Market Data Analytics. September Thoma, M.E. et al. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertility and Sterility (5): Boivin, J. et al. New Debate: International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod (6): WHO. (2013). Meeting to develop a global consensus on preconception care to reduce maternal and childhood mortality and morbidity: World Health Organization Headquarters, Geneva, 6 7 February 2012: meeting report. pp National Health Institute: Fertility Treatments for Females [Online] Available at: treatments/pages/treatments-women.aspx Last accessed: October European Medicines Agency. GONAL-f: EPAR Product Information [Online] Available at: EPAR_-_Product_Information/human/000071/WC pdf Last accessed: October GONAL-f RFF* REDI-JECTTM (follitropin alfa injection) for subcutaneous use Prescribing Information [Online] Available at: gov/drugsatfda_docs/label/2013/021684s036lbl.pdf Last accessed: October PR Newswire, Merck Serono Wins Two Red Dot Design Awards 2015 for High Quality Design of Fertility Pens [press release] Available at: Last accessed: October Merck Serono, Fertility The Real Story, files/f/1452/fertility%20-%20the%20real%20story.pdf 10. Cook-Deegan, R. How Decisions Are Made About Health Research and Health Policy, Stanford University [Online] Available at: class/siw198q/websites/reprotech/new%20ways%20of%20making%20babies/causefem.htm Last accessed: October Serono, Serono Annual Report 2004 [report] [Online] Available at: Last accessed: October Merck, Merck Set to Launch New Version of Fertility Pens [press release] 03 February Available at: EE522B31052D6766C1257F4C0038A469/$File/Pen_2.0_EN.pdf Last access: October Frydman, R. et al. A double-blind, randomized study to compare recombinant human follicle stimulating hormone (FSH; Gonal-F) with highly purified urinary FSH (Metrodin) HP) in women undergoing assisted reproductive techniques including intracytoplasmic sperm injection. The French Multicentre Trialists. Hum Reprod (3): Bassett, R. et al. Continued improvements in the quality and consistency of follitropin alfa, recombinant human FSH. Reprod BioMed Online : Christen, M. et al. The redesigned follitropin alfa pen injector for infertility treatment. Expert Opinion on Drug Delivery Jun 8 (6): Abbotts, C. et al. A redesigned follitropin alfa pen injector for infertility: results of a market research study. Patient Prefer Adherence : Jeannerot, F. et al. Dose accuracy of the redesigned follitropin alfa pen injector for infertility treatment. Expert Opinion on Drug Delivery (12): Zegers-Hochschild, F. et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, Hum Reprod (11): American Society for Reproductive Medicine. The Impact of Age on Female Fertility [Online] Available at: asrm/asrm-content/learning--resources/patient-resources/protect-your-fertility3/age_femaleinfertility.pdf Last accessed: October Petraglia, F. et al. The changing prevalence of infertility. Int J Gynaecol Obstet (2): Agarwal, A. et al. A unique view on male infertility around the globe. Reproductive Biology and Endocrinology 2015 (13): American Pregnancy Association. What is Infertility? [Online] Available at: Last accessed: October 2017 NOVEMBER 2017 GBPMLR/GON/0916/0001(2) 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. 4

5 PRESCRIBING INFORMATION Abbreviated product information based on the GONAL-f EU SPC dated May 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. Indications: (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 gonadotropinreleasing 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. 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 combination treatment may be continued. Current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Contraindications: 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. Precautions: Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of infertility problems. Selfadministration 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. 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

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT GONAL-f 75 IU (5.5 micrograms) powder and solvent for solution for injection. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each