Laboratoires Genevirer Menotrophin IU 1.8.2

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1 Important missing information VI.2 VI.2.1 Elements for a Public Summary Overview of disease epidemiology Infertility is when a woman cannot get pregnant (conceive) despite having regular unprotected sexual intercourse. Infertility is diagnosed when a couple have being unable to conceive after trying for at least 2 years. There are many possible causes of infertility and fertility problems can affect both men and women. Infertility becomes more common with increasing age. Problems with ovulation (the monthly release of an egg) are one of the leading causes of infertility accounting for about 1 in 4 cases of female infertility. One of the most common ovulation disorders to cause infertility is polycystic ovary syndrome (PCOS). PCOS is a condition which makes it more difficult for an egg to be released and accounts for about 73% of infertility cases due to ovulation disorders. Although infertility is not a life-threatening condition, being unable to have a child can cause depression and anxiety for those couples that are affected. VI.2.2 Summary of treatment benefits Fertility treatments are medical techniques which help women to have children. There are three main types of fertility treatments: Medical treatment to restore fertility: this generally involves the use of drugs, such as clomiphene or gonadotrophins, to encourage ovulation. Controlled ovarian hyperstimulation (COH) is a type of medical treatment during which drugs are used to produce multiple ovarian follicles (each follicle is a fluid-filled sac that contains an egg) in one treatment cycle to improve pregnancy rates. COH can be used during assisted conception, described below. Assisted conception: this is also known as assisted reproduction technology (ART) and includes in vitro fertilisation (IVF). This technique involves removing eggs from a woman s body, mixing them with sperm to produce embryos, and then placing these back in the woman s body. This helps conception without the need for vaginal intercourse. Surgical treatments: these can be used to restore fertility. The choice of treatment used depends on the type of infertility that has been diagnosed. EMA/718034/2012 Page 110/159

2 In the UK, about 1 in 7 couples seek medical advice for infertility. Across Europe, the availability of different fertility treatments varies. In particular, different countries have adopted different legal approaches with respect to assisted conception. However, Europe leads the world (excluding Asia) for ART treatment, starting approximately 71% of all reported ART cycles. The impact of successful infertility treatment cannot be underestimated For the purposes of this Summary, we will discuss the first two treatments. For women who are infertile due to ovulation disorders, clomiphene citrate or metformin or a combination of the two medicines are then recommended as the first treatment option toencourage ovulation. Clomiphene citrate may not work in some women and for these patients, another treatment option is to combine clomiphene citrate with metformin, if that is hasn t been already tried, or to have gonadotrophin therapy. Gonadotrophins are hormones which are naturally found in the human body. A type of gonadotrophin that is commonly used for the treatment of infertility is human menopausal gonadotrophin (HMG) which contains three hormones: follicle-stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotrophin (hcg). These hormones stimulate the ovaries to produce follicles which each contain an egg (oocyte). HMG products are well known and have been used as infertility treatment for over 40 years. HMG products are also one of the standard treatments offered to couples as a first option for ensuring controlled ovarian hyperstimulation (COH) when they are undergoing ART such as IVF. Menotrophin LG IU is a new HMG drug which can be used to treat infertility in women with ovulation disorders and for women who are undergoing ART. Main studies: Two clinical studies have been performed to see how effective Menotrophin LG IU is when it is given to women undergoing COH in ART. In both studies, Menotrophin LG IU was compared with another HMG product called Menopur. Menopur is very similar to Menotrophin LG IU. Both medicines were injected under the skin of each patient; this is known as a subcutaneous injection. A total of 427 female patients took part in these studies. Supporting study: In addition, a supporting clinical study was performed with Merional another HMG product which is very similar to Menotrophin LG IU when it is injected either into the muscle or under the skin (sub-cutaneous injection) of women undergoing COH in ART. A total of 168 female patients involved in this study. In the main studies, no detectable differences were seen between Menotrophin LG IU and Menopur. Both treatments produced a similar number of eggs (oocytes) and showed a safe and adequate response. EMA/718034/2012 Page 111/159

3 In the supporting study, no detectable differences were seen between the different injection techniques of subcutaneous and intramuscular. No post-authorisation data are available for Menotrophin LG IU at present because it has not been available on the market for very long. However, other similar HMG products, such as Merional and Menopur, have been successfully used for over 40 years for the treatment of infertility in women so no problems are anticipated for Menotrophin LG IU. VI.2.3 Unknowns relating to treatment benefits In the studies all patients were female, white Caucasians aged between 21 and 40. There is no evidence to suggest that results would be any different in nonwhite patients and this age range is considered to be representative of the women most likely to undergo fertility treatment. The biggest difference in older patients would be the greater likelihood of treatment failure and any safety concerns would be the same as those experienced by the age group of patients who took part in the clinical trials. The women who took part in these studies had a body mass index of between 18 to 30 kgm 2. Women who are under or overweight may have more difficulty in becoming pregnant. Indeed, guidelines in the UK, issued by the National Institute of Health and Clinical Excellence (NICE) recommend that women should be informed that the ideal BMI is in the range kg/m 2 before they start fertility treatment. Although all women undergoing fertility treatment are at potential risk, women with PCOS are at higher risk of experiencing ovarian hyperstimulation syndrome (OHSS). OHSS is a well-known side effect of fertility treatment which causes the ovaries to swell up and produce too many follicles. Women with PCOS did not take part in the clinical studies. However, usage of HMG products that are very similar to Menotrophin LG has shown the safety and effectiveness of these medicines. Furthermore, only licensed clinics or recognised fertility experts are allowed to prescribe these fertility drugs and patients are closely monitored for OHSS. It is standard practice for these clinics carrying out such treatments to have acceptable processes in place to manage OHSS. EMA/718034/2012 Page 112/159

4 VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Swollen ovaries and over production of follicles (ovarian hyperstimulation syndrome) Having more than one baby (e.g. twins) in a single pregnancy (multiple pregnancy) OHSS is a well-known side effect of fertility treatment. The occurrence of OHSS is higher in young women, women with PCOS and in treatment cycles during which conception occurs. In the UK, most cases of OHSS are mild to moderate in severity and affect up to 1 in 20 (5%) of all patients undergoing IVF treatment. More severe cases of OHSS are less common (up to 1 in 100 (0.5-1%) of all IVF cycles) and require hospitalisation to be treated. Severe OHSS normally responds to treatment. Very rarely, OHSS is lifethreatening. After infertility treatment, multiple pregnancies, especially twins, are relatively common. It is the single greatest health risk associated with fertility treatment. In patients undergoing ART, the risk of multiple pregnancy is related to how many embryos are placed inside the woman s body, the quality of these embryos and the patient s age. Legally, doctors are not allowed to transfer more than two embryos if a woman is under the age of 40 and no more than three for women who are aged 40. Women over 40 are at much lower risk of multiple pregnancy and its complications. Only licensed clinics or recognised fertility experts are able to prescribe fertility drugs. Patients are closely monitored for OHSS during fertility treatment. It is standard practice for all clinics carrying out fertility treatment to have acceptable processes in place to manage OHSS. Only licensed clinics or recognised fertility experts are able to prescribe fertility drugs and patients are closely monitored for this known and expected side effect during treatment. For some patients it may not be enough to just inform them about the chance of twin or multiple pregnancy. For these patients, their doctor will provide additional information about the increased risk of serious complications, like birth defects such as cerebral palsy. Skin reactions at the place where the injection is given using a needle (Injection site reactions) A reaction to a needle injection is a known but usually nonserious and mild side effect. The side effects may include one or more of itching, rash, If patients require more than one injection, their doctor will advise them to inject into different places around the body or a smaller needle can EMA/718034/2012 Page 113/159

5 Risk What is known Preventability pain and redness where the needle was injected into the skin. be used. As this is a known side effect of needle injections, the patients will be monitored. EMA/718034/2012 Page 114/159

6 Important potential risks Risk What is known (Including reason why it is considered a potential risk) False pregnancy when the egg implants itself outside the womb (ectopic pregnancy) Loss of pregnancy; abortion or miscarriage (pregnancy wastage) The number of ectopic pregnancies seen after IVF treatment varies between 2-11% of all pregnancies. This is higher than the number reported after natural conception (1%). It is unclear why infertile patients have a higher risk of experiencing an ectopic pregnancy. The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing fertility treatment than those who aren t. Most early pregnancy losses are due to genetic problems in the developing embryo at about 6-8 weeks. Because women who are having fertility treatment know the correct date of the pregnancy test, they will be able to recognise the very early signs of miscarriage more quickly than women who have no fertility problems. A complete abortion is unlikely to cause a life-threatening risk unless a significant amount of blood is lost or infection occurs. Illness may be increased if anaemia or infection develops. Incomplete abortions happen when pregnancy tissue is left in the womb. These are a cause for concern particularly when significant bleeding or infection occurs. If pregnancy tissue is left in the womb, patients may experience symptoms of increased bleeding, increased cramping, and/or infection. Cancer of the reproductive organs (reproductive system neoplasms) Birth defects (congenital malformations) Blood clots (thromboembolic events {TEE}) The seriousness of the condition depends on the type of cancer diagnosed. It should be noted that no link has been confirmed between fertility treatment and cancer. The number of cases of birth defects after ART may be slightly higher than after a natural pregnancy. However, the occurrence of birth defects after fertility treatment still remains rare. In addition, there is no conclusive evidence to link fertility treatment with any specific birth defect. These may affect the arteries or veins. In the veins this may lead to a painful swelling of the legs (deep vein thrombosis) and very occasionally life threatening or fatal clots in the lungs. Clots in the arteries may lead to a heart attack or stroke particularly in patients who already have problems with their arteries. Clots are rare but are a serious complication that can occur during fertility treatment. They are usually associated with OHSS. Other possible causes may be a personal or family history of clots, severe obesity (BMI >30 kg/m 2 ) or your blood has a higher tendency to clot. It should be noted that pregnancy, even without fertility treatment, also carries an increased risk of blood clots developing. Important missing information Not Applicable. EMA/718034/2012 Page 115/159

7 VI.2.5 concern Summary of additional risk minimisation measures by safety All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details of how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PIL). The measures in these documents are known as routine risk minimisation measures. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan Studies which are a condition of the marketing authorisation VI.2.7 Summary of changes to the Risk Management Plan over time EMA/718034/2012 Page 116/159